Research Area: Genetics

Genetic study takes research on sex differences to new heights

Differences in male and female gene expression, including those contributing to height differences, found throughout the body in humans and other mammals.

Greta Friar | Whitehead Institute
July 19, 2019

Throughout the animal kingdom, males and females frequently exhibit sexual dimorphism: differences in characteristic traits that often make it easy to tell them apart. In mammals, one of the most common sex-biased traits is size, with males typically being larger than females. This is true in humans: Men are, on average, taller than women. However, biological differences among males and females aren’t limited to physical traits like height. They’re also common in disease. For example, women are much more likely to develop autoimmune diseases, while men are more likely to develop cardiovascular diseases.

In spite of the widespread nature of these sex biases, and their significant implications for medical research and treatment, little is known about the underlying biology that causes sex differences in characteristic traits or disease. In order to address this gap in understanding, Whitehead Institute Director David Page has transformed the focus of his lab in recent years from studying the X and Y sex chromosomes to working to understand the broader biology of sex differences throughout the body. In a paper published in Science, Page, a professor of biology at MIT and a Howard Hughes Medical Institute investigator; Sahin Naqvi, first author and former MIT graduate student (now a postdoc at Stanford University); and colleagues present the results of a wide-ranging investigation into sex biases in gene expression, revealing differences in the levels at which particular genes are expressed in males versus females.

The researchers’ findings span 12 tissue types in five species of mammals, including humans, and led to the discovery that a combination of sex-biased genes accounts for approximately 12 percent of the average height difference between men and women. This finding demonstrates a functional role for sex-biased gene expression in contributing to sex differences. The researchers also found that the majority of sex biases in gene expression are not shared between mammalian species, suggesting that — in some cases — sex-biased gene expression that can contribute to disease may differ between humans and the animals used as models in medical research.

Having the same gene expressed at different levels in each sex is one way to perpetuate sex differences in traits in spite of the genetic similarity of males and females within a species — since with the exception of the 46th chromosome (the Y in males or the second X in females), the sexes share the same pool of genes. For example, if a tall parent passes on a gene associated with an increase in height to both a son and a daughter, but the gene has male-biased expression, then that gene will be more highly expressed in the son, and so may contribute more height to the son than the daughter.

The researchers searched for sex-biased genes in tissues across the body in humans, macaques, mice, rats, and dogs, and they found hundreds of examples in every tissue. They used height for their first demonstration of the contribution of sex-biased gene expression to sex differences in traits because height is an easy-to-measure and heavily studied trait in quantitative genetics.

“Discovering contributions of sex-biased gene expression to height is exciting because identifying the determinants of height is a classic, century-old problem, and yet by looking at sex differences in this new way we were able to provide new insights,” Page says. “My hope is that we and other researchers can repeat this model to similarly gain new insights into diseases that show sex bias.”

Because height is so well studied, the researchers had access to public data on the identity of hundreds of genes that affect height. Naqvi decided to see how many of those height genes appeared in the researchers’ new dataset of sex-biased genes, and whether the genes’ sex biases corresponded to the expected effects on height. He found that sex-biased gene expression contributed approximately 1.6 centimeters to the average height difference between men and women, or 12 percent of the overall observed difference.

The scope of the researchers’ findings goes beyond height, however. Their database contains thousands of sex-biased genes. Slightly less than a quarter of the sex-biased genes that they catalogued appear to have evolved that sex bias in an early mammalian ancestor, and to have maintained that sex bias today in at least four of the five species studied. The majority of the genes appear to have evolved their sex biases more recently, and are specific to either one species or a certain lineage, such as rodents or primates.

Whether or not a sex-biased gene is shared across species is a particularly important consideration for medical and pharmaceutical research using animal models. For example, previous research identified certain genetic variants that increase the risk of Type 2 diabetes specifically in women; however, the same variants increase the risk of Type 2 diabetes indiscriminately in male and female mice. Therefore, mice would not be a good model to study the genetic basis of this sex difference in humans. Even when the animal appears to have the same sex difference in disease as humans, the specific sex-biased genes involved might be different. Based on their finding that most sex bias is not shared between species, Page and colleagues urge researchers to use caution when picking an animal model to study sex differences at the level of gene expression.

“We’re not saying to avoid animal models in sex-differences research, only not to take for granted that the sex-biased gene expression behind a trait or disease observed in an animal will be the same as that in humans. Now that researchers have species and tissue-specific data available to them, we hope they will use it to inform their interpretation of results from animal models,” Naqvi says.

The researchers have also begun to explore what exactly causes sex-biased expression of genes not found on the sex chromosomes. Naqvi discovered a mechanism by which sex-biased expression may be enabled: through sex-biased transcription factors, proteins that help to regulate gene expression. Transcription factors bind to specific DNA sequences called motifs, and he found that certain sex-biased genes had the motif for a sex-biased transcription factor in their promoter regions, the sections of DNA that turn on gene expression. This means that, for example, a male-biased transcription factor was selectively binding to the promoter region for, and so increasing the expression of, male-biased genes — and likewise for female-biased transcription factors and female-biased genes. The question of what regulates the transcription factors remains for further study — but all sex differences are ultimately controlled by either the sex chromosomes or sex hormones.

The researchers see the collective findings of this paper as a foundation for future sex-differences research.

“We’re beginning to build the infrastructure for a systematic understanding of sex biases throughout the body,” Page says. “We hope these datasets are used for further research, and we hope this work gives people a greater appreciation of the need for, and value of, research into the molecular differences in male and female biology.”

This work was supported by Biogen, Whitehead Institute, National Institutes of Health, Howard Hughes Medical Institute, and generous gifts from Brit and Alexander d’Arbeloff and Arthur W. and Carol Tobin Brill.

Researchers identify important proteins hijacked by pathogens during cell-to-cell spread
Raleigh McElvery
July 9, 2019

Listeria monocytogenes, the food-borne bacterium responsible for listeriosis, can creep from one cell to the next, stealthily evading the immune system. This strategy of cell-to-cell spread allows them to infect many different cell types, and can spur complications like meningitis. Yet the molecular details of this spread remain a mystery.

In a paper recently published in Molecular Biology of the Cell, researchers from the MIT Department of Biology, University of California, Berkeley, and Chan Zuckerberg Biohub are beginning to piece together the elusive means by which Listeria moves from one cell to the next. This mode of transport, the scientists suggest, looks a lot like trans-endocytosis, a process that healthy, uninfected cells use to exchange organelles and various cytoplasmic components. In fact, the two processes are so similar that Listeria may be co-opting the host cell’s trans-endocytosis machinery for its own devices.

Although the particulars of trans-endocytosis are poorly understood, the process permits neighboring cells to exchange materials via membrane-bound compartments called vacuoles, which release their cargo upon reaching their final destination.

Much like trans-endocytosis, cell-to-cell spread relies on vacuoles to ferry Listeria. First, the pathogen commandeers the host cell’s own machinery to assemble a tail of proteins that allows it to rocket around inside the cell and ram against both the membrane of the host and that of the adjacent cell. The resulting protrusion is then somehow engulfed into a double-membrane vacuole, and the bacteria burst through their containment to begin the process anew in the recipient cell.

“There’s been a lot of work looking at Listeria cell-to-cell spread,” says Rebecca Lamason, the Robert A. Swanson (1969) Career Development Assistant Professor in the MIT Department of Biology and senior author on the study. “But we still don’t really understand the molecular mechanisms that allow the bacteria to manipulate the membrane to promote engulfment. Depending on what we uncover, we might also be able to apply that information to better grasp how an uninfected cell regulates trans-endocytosis.”

Lamason and her team anticipated that the same proteins implicated in trans-endocytosis would also be involved in Listeria cell-to-cell spread, which would indicate that the pathogen was appropriating these proteins for its own purposes. The researchers made a list of 115 host genes of interest, and then used an RNAi screen to identify just 22 that are critical for cell-to-cell spread.

They were excited to find that, of those 22 genes, several are also implicated in endocytosis, which suggests Listeria is using a similar strategy. These include genes encoding caveolin proteins that control membrane trafficking and remodeling, as well as another protein called PACSIN2 that interacts with caveolins to regulate protrusion engulfment.

Now that the researchers have pinpointed these key proteins, the next step is to determine how they work together in order to promote cell-to-cell spread — especially since the protrusions created by Listeria are much larger than those required for trans-endocytosis.

“As we drill down even deeper into the molecular mechanisms, it will be interesting to see where trans-endocytosis and cell-to-cell spread differ, and where they are similar,” Lamason says. “Our hope is that investigating the mechanisms of bacterial spread will reveal fundamental insights into host intercellular communication.”

Citation:
“RNAi screen reveals a role for PACSIN2 and caveolins during bacterial cell-to-cell spread”
Molecular Biology of the Cell, online June 26, 2019, DOI: 10.1091/mbc.E19-04-0197
Allen G. Sanderlin, Cassandra Vondrak, Arianna J. Scricco, Indro Fedrigo, Vida Ahyong, and Rebecca L. Lamason

Unusual labmates: Lighting up the lab
July 7, 2019

Unusual Labmates is a series that explores some of the more unusual models used for research at Whitehead Institute. From rare plants to luminescent beetles to regenerative starfish and worms, these organisms and their unusual traits provide insights into the underlying biology and incredible diversity of living things.

Massachusetts Institute of Technology (MIT) graduate student Tim Fallon is standing in a field in New Jersey, holding a net and waiting for the last glimmers of sunlight to disappear. As the trees surrounding the field fade into shadow, Fallon watches the ground intently. The air is still and then, hovering above the grass, a small point of light appears. It floats through the air in a concave upwards arc and winks out. Soon, more lights follow suit. These are fireflies, unassuming beetles by day, but at night they put on a dazzling luminescent display in the hope of attracting a mate. Fallon sweeps his net through the air, capturing some of them. He has traveled to New Jersey with other members of Whitehead Institute Member and associate professor of biology at MIT Jing-Ke Weng’s lab to collect specimens of Photinus pyralis, the big dipper firefly, in order to sequence a firefly genome for the very first time.

Fireflies have been around for more than one hundred million years, and in that time have diverged into more than 2,000 species and spread to every continent except Antarctica. The beetles (despite their name, fireflies are actually beetles) are widely known, and often beloved, for their enchanting courtship rituals, but they have also piqued the interest of scientists, who have harnessed the gene behind their light emitting capability for use in research. However, for all of fireflies’ appeal, they are a difficult animal to work with in the lab, and much of their biology remains shrouded in mystery. In the hopes of improving that situation, Weng, Fallon, and collaborators—including Sarah Lower, assistant professor of biology at Bucknell University, and Yuichi Oba, professor at Chubu University in Japan—have been investigating fireflies, primarily by sequencing and analyzing their genomes. This research is providing insights into the evolution of fireflies’ light-producing ability, the biomolecular pathways the fireflies use to luminesce, and could perhaps even inform how the use of firefly-based luminescence in research can be improved.

The chemistry of light

Fireflies produce light using two main ingredients: an enzyme called luciferase and the small molecule luciferin. Luciferase facilitates a chemical reaction that oxidizes the luciferin, and one product of the reaction is light. In the 1980s, researchers recreated the process in plants and plant cells by cloning the firefly gene responsible for the luciferase enzyme from big dipper fireflies and then inserting it into the genomes of their specimens in the lab.[1] When they injected luciferin into the specimens, they began to glow – just like fireflies. Researchers now use this approach in both plant and animal models to track various aspects of biology. They can link the luminescence to a trait or process, and then measure the level of light emitted. For example, researchers can fuse the luciferase gene to a gene of interest such that the two genes will be expressed as one. Then they introduce luciferin to the system and measure the light output using very sensitive equipment that can sense minute changes. The more light that is emitted, the higher the activity level of both luciferase and the gene of interest. This is a widely used assay that, Fallon says, every biologist uses or at least learns about during their training. Luciferase-luciferin has many applications, and along with tracking gene expression it has also been used to track cancer metastasis, monitor medical treatment efficacy, and check for microbial contamination—including on space vehicles such as the Mars Curiosity Rover.[2] The extreme sensitivity of luciferin-luciferase tests makes them an attractive choice in many experiments.

In spite of the widespread use of firefly luminescence, a lot about it still isn’t known, especially when it comes to luciferin. While the gene encoding luciferase has been identified, luciferin is thought to be created through a process involving multiple genes, and the complete set of those genes is unknown, as are the steps involved in the production of luciferin: the intermediate molecules produced and how they are modified to reach the final product. Although Weng’s lab generally studies plants and focuses on understanding how plants evolved biochemical pathways to produce unique small molecules with traits of interest, particularly those with medicinal value, when Fallon joined the lab, he convinced Weng that investigating the unknowns of the small molecule luciferin was a similar and suitable project.

Fireflies in the wild

When Fallon joined the Weng lab, there were not a lot of research tools available for investigating fireflies, starting with the lack of a sequenced genome. Only a handful of firefly genes had even ever been identified. Weng and his collaborators crowdfunded the money to sequence the first firefly genome, and then received funding to sequence a second firefly species and a bioluminescent click beetle, providing a wealth of new data to explore.

The lack of tools for firefly research was due in part to how difficult it is to rear fireflies in the lab, which makes them tricky animals to study. Fireflies are very sensitive to changes in their environments, and in the lab it’s difficult to mimic the right vegetation, climate, seasonal shifts, and other factors that the beetles rely on to time their metamorphoses and thrive.

Unpredictable environmental changes are becoming a common challenge for fireflies beyond the lab as well, due to the impact of humans on their habitats. Fireflies’ sensitivity to these changes may be causing their disappearance. Anecdotally, many people have fond memories of seeing fireflies every summer when they were younger and can attest to the absence of fireflies in those same places now. A large citizen science research project called Firefly Watch is currently underway to figure out the extent to which firefly populations are declining across the United States (U.S.).[3] And in a case indicative of a larger problem, conservation groups recently submitted an urgent petition to recognize the Bethany Beach firefly, whose key habitat in Delaware is at risk due to human development, as the first endangered firefly species in the U.S.[4]

A significant manmade disruption to the fireflies’ habitats is light pollution. Fireflies find each other by signaling with light, but their lanterns are no match for electricity; a firefly trying to outshine a streetlamp might as well be facing off with the sun. For species that evolved faint glows to flash in the dead of night, in the dark of forests, finding a place where their light can be seen is getting harder and harder. Big dipper fireflies have fared better than many others species. They’re large, with bright lanterns, and they tend to flash at twilight, so they are used to competing with some ambient light. Unsurprisingly, big dipper fireflies remain abundant in the wild, including in and near cities. They can be spotted all over the eastern and midwestern U.S., where they are easily identifiable thanks to the distinctive J-shape—resembling the curve of a dipper—that they make as they flash.

Big dipper fireflies have been important in biology research—it is from them that the firefly luciferase gene was first cloned—and so they were the first species that Fallon and his collaborators chose for their genome sequencing project. However, big dipper fireflies fare no better than other firefly species in a lab setting. No one has ever successfully reared big dipper fireflies through a full lifecycle (from egg to egg) in the lab, Fallon says. So, in spite of the ease of collecting big dipper fireflies in the eastern U.S., in order to get a population of fireflies going in the lab, Fallon had to look elsewhere: to Japan.

In Japan, fireflies are beloved. Watching them is a popular summer pastime, and they are celebrated in myths, songs, and other media. The two dominant species are both aquatic in their larval stages: the heike-botaru (Aquatica lateralis), which mostly lives in flooded rice paddy fields, and the larger and brighter genji-botaru (Luciola cruciata), which lives in streams and rivers. Both species need clean bodies of water to survive, and so their numbers have diminished in cities—but unlike in America, Japan has not allowed fireflies to fade away quietly into the night. As fireflies have grown scarcer, breeding centers have begun rearing the insects in large numbers, using big facilities that can recreate the fireflies’ natural habitat on a scale not possible in a U.S. lab. Fireflies are sometimes bred for conservation purposes, such as an effort to bolster the heike population in the water by the Imperial Palace in Tokyo. The fireflies are also bred for spectacle, released during summer festivals and firefly-watching events in the city to recreate the lost experience of glow-filled nights. The Fussa firefly festival has drawn large crowds for more than fifty years.

Rearing insects is also a relatively common pastime in Japan. When Fallon was looking for a type of firefly that would be a good addition to the genome sequencing project and could survive in lab conditions, he learned of the heike, which are kept in captivity and used in research in Japan. Although heike are still very sensitive to small changes in their environments, they have been demonstrated to survive for multiple generations indoors, unlike the big dipper firefly. The larvae are aquatic, and maintaining a controlled aquarium is also easier than a terrarium, Fallon says. Fallon received his fireflies from a collaborator in Japan, firefly expert Dr. Yuichi Oba, a professor at Chubu University. Oba works with Haruyoshi Ikeya, a high school teacher in Yokohama, Japan who cracked the code of rearing heike fireflies indoors several decades ago; the population from which Fallon received his specimens has been lab-bred since its original capture in 1990. Fallon received tips from Oba on how to successfully rear the fireflies—though not all of these could be followed, due to stricter regulations for how to keep the fireflies contained in the U.S., where the United States Department of Agriculture considers them a potential plant pest.

Fireflies in the lab

Fallon rears the fireflies in a small room separate from the main space of the Weng lab. The room is tightly packed with supplies and various aquariums: Fallon must move the firefly specimens between environments as they go through their lifecycle. There is tinfoil over the windows so when Fallon switches the lights off the room becomes a darkroom, where he can observe the fireflies flashing.

Maintaining a lab population serves a number of purposes. First of all, collecting fireflies is time-consuming, limited by season, and in the case of foreign species, involves further transportation and regulatory roadblocks. When collecting specimens in the wild, it’s easy to find adults, but harder to get access to every stage of the lifecycle, especially eggs and pupae, the way you can in the lab. Having a lab population also ensures that you are working with one species, whereas when collecting in the wild it can be easy to get a mixed-up batch—one field may contain a dozen similar-looking species—and molecular biology research requires species-specific material. Overall, having a lab population means access to live specimens whenever you need them: whenever the researchers have a new research question to answer or a new experiment to run. However, maintaining this beneficial resource is not a simple feat.

Rearing fireflies in captivity is difficult in part because each stage of their life cycle has different requirements. Fireflies hatch from eggs, which the heike lay in moss near water. Heike larvae live in water, where they spend most of their lifespan, usually around one year, though in the lab this stage can be as short as six months. During this time, the larvae typically go through five or six instars, or stages of growth between molting. Insects must molt in order to grow, as their size is restricted by their exoskeletons. The heike’s first instar is only a few millimeters long, while the final instar may grow to be closer to two centimeters.

For most of their time as larvae, the specimens live in shoebox sized aquariums inside a metal cabinet. Fallon feeds them bladder snails and waits for them to grow. When the larvae are in their later instars, around the right size and age to pupate, Fallon moves them into another aquarium with a mock riverbank inside, with a soil mixture devised by Haruyoshi Ikeya. The riverbank is necessary because the firefly larvae move to land to pupate. First, they begin to exhibit what is called climbing or landing behavior, during which they will flash—fireflies are capable of emitting light at all stages of their lifecycle. The flashes may be a signal to help coordinate pupation. If a larva doesn’t synchronize with the others when it is ready to pupate, there won’t be any mates around when it hatches. Fireflies don’t live very long as adults, so they must find a mate quickly. In the lab, once the adults hatch, Fallon moves them into another container to prevent them from drowning in the water of the mock river, and hopes that they mate. If they are successful, then the female lays her eggs in the moss Fallon provides, starting the cycle over again.

The fireflies are not easy to keep alive in lab conditions, so the researchers have been experimenting with different conditions for rearing them, like keeping them in boxes of different sizes, changing the aeration of their water, and providing different spaces for the adults to rest when they first hatch.

“We’ve been iterating through a lot of different ways to rear them,” Fallon says. “It’s not like with fruit flies, where you could leave two alone in a room with a banana, and soon you’ve got more fruit flies than you know what to do with. The fireflies are really quite finicky. Over time we’re learning what works and what doesn’t.”

One thing that Fallon has learned from rearing fireflies is how often they glow, during every part of their life cycle. The heike lay their eggs in clumps, which are cumulatively visible to the naked eye. Big dipper firefly eggs also luminesce, but faintly enough that it’s only visible using a sensitive camera. If there’s an evolutionary advantage to having the eggs luminesce, it’s not known. The larvae’s ability to glow is typically believed to be, at least in part, an aposematic signal: a warning to potential predators that the larvae are toxic so the predators won’t try to eat them. Other species use bright colors for the same purpose—think of brilliantly colored poison dart frogs or the popular mnemonic “red touches yellow kills a fellow” used to identify venomous coral snakes—and what’s brighter than something that glows in the dark?

Fireflies’ toxicity comes from chemicals called lucibufagins. Only some firefly species produce these, though the rest may benefit by association if predators associate glowing beetles with a bitter meal. Fallon has noticed that the heike larvae will glow anytime they appear threatened or are faced with the unfamiliar, like if he jostles the box they live in. This threat response is consistent with the expectations for an aposematic signal, but the heike larvae also glow in other conditions, such as during their climbing behavior right before they pupate—and the pupae glow as well. The adults, meanwhile, can also warn off predators with their flashes but primarily luminesce to communicate and find a mate. Different firefly species have distinct flash patterns, as do males and females, allowing adults to identify a suitable partner—and allowing anyone with enough firefly knowledge to identify different species just by watching their flashes.

In every stage of life, fireflies have adapted to make the most of their light-emitting ability. Once they had the genome sequences and firefly specimens in hand, Weng and Fallon wanted to find out how.

What can we learn from fireflies?

The researchers used the firefly genomes to delve into the biomolecular pathways that fireflies use to create light. They identified a luciferin-derived molecule in fireflies that may be a storage form for luciferin, as well as the gene encoding the enzyme that converts luciferin into this molecule. They have also been looking into fireflies’ mechanism for recycling luciferin. The one significant handicap of using luciferase-luciferin in research is that, since the genes encoding luciferin are unknown, the chemical must be fed or injected into specimens manually. This limits the duration of experiments based on when the luciferin is used up, or requires disrupting specimens to reinject them. In the wild, fireflies are able to reuse their luciferin molecules after they have been oxidized to produce light; if researchers could figure out how they do this, it could potentially be applied in the lab.

One major mystery surrounding fireflies that the researchers wanted to solve was whether beetles evolved the ability to luminesce once, or multiple times. Fireflies are one of at least four beetle families that can luminesce—the others are click beetles (Elateridae), glowworm beetles or railroad worms (Phengodidae), and starworms (Rhagophthalmidae). These different beetles all use similar chemistry to luminesce: similar luciferase enzymes and structurally identical luciferins. This commonality suggests that luminescence evolved in a shared ancestor of the four families, and was lost in other related beetles that do not luminesce. However, as Charles Darwin noted, the families of luminescent beetles are very different morphologically, including having distinct light organs—the click beetle emits light from lanterns by its head, whereas the fireflies emit light from their rears. These dissimilarities in shape suggested that the beetle families each evolved luminescence separately; if the light organs evolved from a common ancestor, researchers would expect them to resemble each other. Complicating the matter is that not every species in these families can luminesce; while all known fireflies can emit light, only some click beetles can. This suggests that even within the bioluminescent beetle families, luminescence has evolved multiple times, or been lost multiple times, or some combination thereof.

In order to solve this puzzle, the researchers sequenced the genome of three beetles and compared them: the big dipper firefly, the heike firefly, and the cucubano click beetle (Ignelater luminosus), which is also capable of luminescence. The last common ancestor of heike and big dipper fireflies lived over 100 million years ago, making them good candidates for evolutionary comparison. The researchers found evidence that fireflies and click beetles evolved luminescence independently. They pinpointed where the luciferase gene was in each species’ genome, and what its neighbors were—in the fireflies, the gene was surrounded by genes involved in fatty acid metabolism, suggesting that it evolved from one of these. Meanwhile, the researchers found the click beetle’s luciferase gene in a completely different genetic neighborhood, suggesting that it evolved separately and from a different ancestral gene.

It may seem unusual for such an extraordinary trait as luminescence to have evolved multiple times, but in fact it is a trait that evolution constantly stumbles upon, Fallon says. Beetles are far from the only creatures capable of emitting light; bioluminescence has also evolved in many niches, including in species of fish, coral, jellyfish, squid, snails, fungi, and bacteria.

Fireflies’ luminescence is not a unique trait, but it’s one worth preserving. From fireflies lighting up the night sky at summer festivals and in backyards, to children chasing them through the grass trying to capture a little magic in their hands, to researchers exploring biology with the help of the ultra-sensitive luciferase gene, people benefit from sharing our world with these dazzling little beetles. With the new data coming out of labs like Weng’s, further research benefits from fireflies’ light-making machinery may be on the horizon.

Fallon has learned a lot about the difficulties of rearing fireflies as he tries to maintain a sustainable population in the lab; meanwhile conservationists are struggling to protect populations of fireflies out in the wild. Even the wild population from which Fallon’s fireflies were originally captured no longer exists. Though the species survives, that particular population’s habitat disappeared, leaving the lab-bred beetles as their only legacy. The more that researchers learn about fireflies, the better equipped we may be to protect them from the sort of environmental vulnerabilities that killed off the Weng lab fireflies’ ancestors—both for the sake of the fireflies themselves, and for own sake as spectators and researchers.

Credits

Written by Greta Friar

Video by Conor Gearin

Audio production by Conor Gearin

Cover video by Radim Schreiber / FireflyExperience.org

“The chemistry of light” title card photo by Tim Fallon

“Fireflies in the wild” title card photo by Radim Schreiber / FireflyExperience.org

“Fireflies in the lab” title card photo by Conor Gearin

“What can we learn from fireflies?” title card photo by Conor Gearin

Special thanks to Radim Schreiber, Tim Fallon and Jing-Ke Weng

Works cited:

[1] https://science.sciencemag.org/content/234/4778/856

[2] https://www.science.gov/topicpages/p/planetary+protection+protocols

[3] https://www.massaudubon.org/get-involved/citizen-science/firefly-watch

[4] https://xerces.org/2019/05/15/bethany-beach-firefly/

Pulin Li

Education

  • PhD, 2012, Chemical Biology, Harvard University
  • BS, 2006, Life Sciences, Peking University

Research Summary

We are fascinated by how and why cells organize into spatial patterns within tissues, aiming to uncover the fundamental design principles that govern tissue form and function. To explore this, we adopt a bottom-up approach to reconstitute multicellular patterns in vitro using synthetic biology tools, guided by mathematical modeling. In parallel, we study how patterns emerge in natural tissues and investigate their functional roles, using a combination of quantitative imaging, mouse genetics, machine learning, and stem cell engineering. Our current focus is on the patterning of the embryonic and adult lung. Through these complementary efforts, we strive to achieve a quantitative, multi-scale understanding of tissue development and to create new strategies for tissue engineering.

Awards

  • Teaching Prize for Undergraduate Education, MIT School of Science, 2023
  • Allen Distinguished Investigator, The Paul Alen Frontiers Group, 2021
  • New Innovator Award, National Institutes of Health Common Fund’s High-Risk, High-Reward Research Program, 2021
  • R.R. Bensley Award in Cell Biology, American Association for Anatomy, 2021
  • Santa Cruz Developmental Biology Young Investigator Award, 2016
  • NIH Pathway to Independence Award K99/R00 (NICHD), 2016
  • American Cancer Society Postdoctoral Fellowship, 2015
Measuring chromosome imbalance could clarify cancer prognosis

A study of prostate cancer finds “aneuploid” tumors are more likely to be lethal than tumors with normal chromosome numbers.

Anne Trafton | MIT News Office
May 13, 2019

Most human cells have 23 pairs of chromosomes. Any deviation from this number can be fatal for cells, and several genetic disorders, such as Down syndrome, are caused by abnormal numbers of chromosomes.

For decades, biologists have also known that cancer cells often have too few or too many copies of some chromosomes, a state known as aneuploidy. In a new study of prostate cancer, researchers have found that higher levels of aneuploidy lead to much greater lethality risk among patients.

The findings suggest a possible way to more accurately predict patients’ prognosis, and could be used to alert doctors which patients might need to be treated more aggressively, says Angelika Amon, the Kathleen and Curtis Marble Professor in Cancer Research in the Department of Biology and a member of the Koch Institute for Integrative Cancer Research.

“To me, the exciting opportunity here is the ability to inform treatment, because prostate cancer is such a prevalent cancer,” says Amon, who co-led this study with Lorelei Mucci, an associate professor of epidemiology at the Harvard T.H. Chan School of Public Health.

Konrad Stopsack, a research associate at Memorial Sloan Kettering Cancer Center, is the lead author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of May 13. Charles Whittaker, a Koch Institute research scientist; Travis Gerke, a member of the Moffitt Cancer Center; Massimo Loda, chair of pathology and laboratory medicine at New York Presbyterian/Weill Cornell Medicine; and Philip Kantoff, chair of medicine at Memorial Sloan Kettering; are also authors of the study.

Better predictions

Aneuploidy occurs when cells make errors sorting their chromosomes during cell division. When aneuploidy occurs in embryonic cells, it is almost always fatal to the organism. For human embryos, extra copies of any chromosome are lethal, with the exceptions of chromosome 21, which produces Down syndrome; chromosomes 13 and 18, which lead to developmental disorders known as Patau and Edwards syndromes; and the X and Y sex chromosomes. Extra copies of the sex chromosomes can cause various disorders but are not usually lethal.

Most cancers also show very high prevalence of aneuploidy, which poses a paradox: Why does aneuploidy impair normal cells’ ability to survive, while aneuploid tumor cells are able to grow uncontrollably? There is evidence that aneuploidy makes cancer cells more aggressive, but it has been difficult to definitively demonstrate that link because in most types of cancer nearly all tumors are aneuploid, making it difficult to perform comparisons.

Prostate cancer is an ideal model to explore the link between aneuploidy and cancer aggressiveness, Amon says, because, unlike most other solid tumors, many prostate cancers (25 percent) are not aneuploid or have only a few altered chromosomes. This allows researchers to more easily assess the impact of aneuploidy on cancer progression.

What made the study possible was a collection of prostate tumor samples from the Health Professionals Follow-up Study and Physicians’ Health Study, run by the Harvard T.H. Chan School of Public Health over the course of more than 30 years. The researchers had genetic sequencing information for these samples, as well as data on whether and when their prostate cancer had spread to other organs and whether they had died from the disease.

Led by Stopsack, the researchers came up with a way to calculate the degree of aneuploidy of each sample, by comparing the genetic sequences of those samples with aneuploidy data from prostate genomes in The Cancer Genome Atlas. They could then correlate aneuploidy with patient outcomes, and they found that patients with a higher degree of aneuploidy were five times more likely to die from the disease. This was true even after accounting for differences in Gleason score, a measure of how much the patient’s cells resemble cancer cells or normal cells under a microscope, which is currently used by doctors to determine severity of disease.

The findings suggest that measuring aneuploidy could offer additional information for doctors who are deciding how to treat patients with prostate cancer, Amon says.

“Prostate cancer is terribly overdiagnosed and terribly overtreated,” she says. “So many people have radical prostatectomies, which has significant impact on people’s lives. On the other hand, thousands of men die from prostate cancer every year. Assessing aneuploidy could be an additional way of helping to inform risk stratification and treatment, especially among people who have tumors with high Gleason scores and are therefore at higher risk of dying from their cancer.”

“When you’re looking for prognostic factors, you want to find something that goes beyond known factors like Gleason score and PSA [prostate-specific antigen],” says Bruce Trock, a professor of urology at Johns Hopkins School of Medicine, who was not involved in the research. “If this kind of test could be done right after a prostatectomy, it could give physicians information to help them decide what might be the best treatment course.”

Amon is now working with researchers from the Harvard T.H. Chan School of Public Health to explore whether aneuploidy can be reliably measured from small biopsy samples.

Aneuploidy and cancer aggressiveness

The researchers found that the chromosomes that are most commonly aneuploid in prostate tumors are chromosomes 7 and 8. They are now trying to identify specific genes located on those chromosomes that might help cancer cells to survive and spread, and they are also studying why some prostate cancers have higher levels of aneuploidy than others.

“This research highlights the strengths of interdisciplinary, team science approaches to tackle outstanding questions in prostate cancer,” Mucci says. “We plan to translate these findings clinically in prostate biopsy specimens and experimentally to understand why aneuploidy occurs in prostate tumors.”

Another type of cancer where most patients have low levels of aneuploidy is thyroid cancer, so Amon now hopes to study whether thyroid cancer patients with higher levels of aneuploidy also have higher death rates.

“A very small proportion of thyroid tumors is highly aggressive and lethal, and I’m starting to wonder whether those are the ones that have some aneuploidy,” she says.

The research was funded by the Koch Institute Dana Farber/Harvard Cancer Center Bridge Project and by the National Institutes of Health, including the Koch Institute Support (core) Grant.

A supportive role for planarians’ multifaceted muscle
Greta Friar | Whitehead Institute
April 5, 2019

CAMBRIDGE, MA  — Planarians are flatworms best known for their incredible ability to regenerate all their body parts: chop a planarian in two and soon you will have two perfectly formed planarians. As Whitehead Institute Member Peter Reddien, also a professor of biology at Massachusetts Institute of Technology and an investigator with the Howard Hughes Medical Institute, has investigated planarians over the years, he has become increasingly fascinated with the functions of their muscle. Not only do planarians use muscle to move, but Reddien’s research group previously discovered they rely on muscle tissue to provide a full body map with instructions that helps guide stem cells to the right locations during both regeneration and normal turnover of cells. Muscle tissue does this by secreting positional signals that help cells identify where they are — and where they should be.

New research from Reddien and graduate student Lauren Cote shows that muscle serves yet another crucial function in planarians. In a paper published in Nature Communications on April 8, they show that muscle operates as the planarian’s connective tissue, providing basic architectural support for the body. Connective tissue functions in large part by secreting molecules that make up the extracellular matrix (ECM), a network of molecules outside of the body’s cells that provides tissues with, among other things, scaffolding, protection, separation of tissues, and a means of inter-tissue connection and communication. In vertebrates, including humans, connective tissue is a distinct tissue type containing dedicated cells such as fibroblasts that secrete most of the animal’s ECM proteins. Reddien and Cote found no such fibroblast-like cell type in planarians; instead, multipurpose muscle does it all.

The researchers began to suspect that planarian muscle might function as connective tissue when they discovered that the gene encoding a major type of ECM molecule, fibrous protein collagen, was expressed only in muscle. The researchers then catalogued the total collection of proteins found in the planarian’s ECM, called the matrisome, and tracked where the genes that code for those proteins were expressed. They identified nineteen collagen genes, and all nineteen were highly specific to muscle. The vast majority of other ECM genes followed suit.

To further test muscle’s role as connective tissue, the researchers silenced the gene hemicentin-1, which produces another ECM molecule expressed specifically in muscle. They found that when the gene was not expressed, the planarian’s inner tissues did not remain properly separated from its outer skin. In other words, a muscle-specific gene is necessary in the planarians they studied for the core connective tissue task of keeping tissues discrete.

Although it might seem unusual that planarians would use muscle tissue for both ECM secretion and body pattern maintenance, Reddien and Cote say the combination makes a certain sense.

“To establish a map of the body, muscle secretes positional signals, and in its role as connective tissue it is simultaneously creating the extracellular environment the signals travel through,” Reddien says.

Cote agrees: “Producing the body’s physical architectural support and its biochemical architectural blueprint seem to go hand in hand.”

One possibility raised by this synchronicity is that a link between connective tissue and harboring positional information exists broadly across animal species. Studies elsewhere have found some positional role or positional memory in connective tissues in several species, including axolotls, vertebrates capable of limb regeneration. Based on these observations, Reddien says, it would be interesting to consider the positional role that connective tissue cells, like fibroblasts, might play in humans and might have in instructing regeneration broadly.

 

Written by Greta Friar

 

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Peter Reddien’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute Investigator and a professor of biology at Massachusetts Institute of Technology. The authors also acknowledge the Eleanor Schwartz Charitable Foundation for support.

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Full citation:

“Muscle functions as a connective tissue and source of extracellular matrix in planarians”

Nature Communications, online April 8, 2019. DOI: 10.1038/s41467-019-09539-6

Lauren E. Cote, Eric Simental, and Peter W. Reddien.

A Troubling Inheritance
Greta Friar | Whitehead Institute
April 9, 2019

CAMBRIDGE, MA — Cancers have a habit of running in the family. This is due in large part to the inheritance of versions of genes that are linked with cancer, but some researchers are investigating another heritable risk factor: epigenetic modifications. These are not changes in the DNA sequence of a gene itself but rather are processes that change a DNA sequence’s accessibility or ability to be expressed. These changes can regulate gene expression, and in certain circumstances, be passed down from parent to child alongside the genes they regulate. New research published in eLife on April 9 from the lab of Whitehead Member and Institute Director David Page, also a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes Medical Institute investigator, and colleagues has found evidence that when atypical epigenetic modifications, or marks, caused by a gene deletion in the parent’s cells, are inherited it can lead to increased cancer incidence and shorter lifespans in mice.

Studying epigenetic inheritance in mammals can be difficult because mammalian embryos undergo strong epigenetic reprogramming, a kind of “erasing and starting over” for the next generation. Some of the parents’ epigenetic marks resist this reprogramming, but the vast majority are erased, and often what may appear to be epigenetic inheritance can be explained by other factors like environmental exposures during fetal development leading to similar epigenetic profiles.

“We had to design an experiment with a specific, well-defined initiating event, so the epigenetic patterns and health effects would be easy to track,” says first author Bluma Lesch, then a postdoctoral researcher in the Page lab at Whitehead Institute and now an assistant professor of Genetics at Yale School of Medicine and a member of the Genomics, Genetics and Epigenetics Program at Yale Cancer Center.

In order to do this, the researchers first deleted Kdm6a (also called Utx), a gene on the X chromosome that encodes a protein involved in epigenetic regulation, in the male mouse germline—the repository of cells that become sperm. Kdm6a removes epigenetic modifications from histones, the spool-like proteins that house strands of DNA. Deleting Kdm6a led to higher than usual levels of specific types of histone modifications in the genome of the mice’s sperm, which in turn prompted a secondary epigenetic shift, an increase in DNA methylation—the addition of a methyl group to DNA that can alter gene expression.

The researchers used the hypermethylated sperm to create a generation of offspring. A crucial aspect of the experiment was creating offspring that inherited the atypical epigenetic marks but not the gene deletion that caused them in order to uncouple the effects of the two changes. Offspring were bred from a modified male germline and an unmodified female germline, so male offspring inherited a healthy X chromosome from their mothers, and an unaffected Y chromosome from their fathers. Genetically, the mice were normal, but they were formed from sperm that had been exposed to the Kdm6a deletion’s epigenetic effects.

When the researchers studied the epigenome of these offspring, they found that while many of the modifications had been erased due to reprogramming, more than 200 of the sections of DNA that had been hypermethylated in the father’s germline following Kdm6a deletion were likewise hypermethylated in the offspring. That persistence is much higher than would be expected by chance or observed in normal mice. The researchers found matching instances of hypermethylation in the offspring’s bone marrow, liver tumors, and spleen, indicating that the inherited epigenetic changes stuck with the offspring though embryonic development into adulthood. The researchers did not pinpoint the mechanism that allowed these epigenetic marks to resist reprogramming; Lesch hopes to pursue that question in the future.

Then the researchers watched the mice grow, waiting to see how the unusual DNA methylation would affect the mice’s health. For a while, the mice appeared perfectly healthy — until they hit middle age. The mice then began developing tumors, experiencing an increase in cancer incidence and a decrease in lifespan.

To get a better understanding of the effects they were seeing, Page and Lesch sought help from cancer experts Benjamin Ebert, chair of medical oncology at the Dana Farber Cancer Institute (DFCI) and member of the Broad Institute; Zuzana Tothova, DFCI investigator and associate member of the Broad Institute; and Roderick Bronson, veterinary pathologist at Harvard Medical School. The experts helped characterize the mice’s diseases. Instead of becoming more susceptible to one specific type of cancer, the mice had a diverse set of diagnoses, similar to what would be expected of normal mice at a much older age. The researchers believe this is due to hypermethylation that they observed in enhancers, regions of DNA that help increase transcription of many genes but are also commonly implicated in cancer.

Although the researchers cannot say whether the same sort of epigenetic inheritance is occurring in humans, they believe that this is a valuable question for future research. Inherited epigenetic marks would not appear in a typical genetic screen for cancer risk, and as such could be overlooked to the detriment of preventative care. Likewise, the researchers note, cancer drugs that target epigenetic mechanisms are on the rise, and there has been no research into the effects that this might have on children conceived by people taking the drugs. If human embryos are inheriting aberrant epigenetic marks in the manner observed in mice in this investigation, then people taking drugs with epigenetic targets should be warned against conceiving children until after they are clear of the effects of their medication.

“We hope that this research demonstrating the cancer risk of inherited epigenetic marks in mice adds to the burgeoning field of mammalian epigenetic inheritance research,” Page says, “and that we have drawn attention to the possible implications for human health.”

 

Written by Greta Friar

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David Page’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute Investigator and a Professor of Biology at the Massachusetts Institute of Technology.

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Full citation:

“Intergenerational epigenetic inheritance of cancer susceptibility in mammals”

eLife, April 9, 2019, DOI: https://doi.org/10.7554/eLife.39380

Bluma J. Lesch, Zuzana Tothova, Elizabeth A. Morgan, Zhicong Liao, Roderick T. Bronson, Benjamin L. Ebert, and David C. Page.

Scaffolding the nursery of pollen development
Nicole Giese Rura | Whitehead Institute
April 2, 2019

Cambridge, MA — Increased temperatures and decreased precipitation associated with climate change could threaten the world’s crops. Seed and pollen production in particular are vulnerable to shifts in temperature or rainfall. For example, in heat- or drought-stressed wheat and rice, the tissue responsible for nourishing pollen, called the tapetum, is compromised, causing the plants to not generate pollen. Without pollen, these staples are unable to bear the grains that billions of people rely on for food. In research described this week in the journal Plant Cell, Whitehead Institute Member Jing-Ke Weng and his lab have identified the components of a critical scaffold system that supports the tapetum. With a better understanding of the tapetum, scientists may be able to adapt plants to produce pollen even in hot, arid conditions.

Within a flower bud, pollen-filled anthers perch atop stalk-like filaments. Lining the anther’s inner chamber is a tissue called the tapetum, which nurtures the developing pollen. To better understand pollen and anther formation, Joseph Jacobowitz, a graduate student in Weng’s lab and first author of the Plant Cell paper, analyzed genes active in the anther during early flower development in the Arabidopsis plant. Two practically unknown genes stood out because they likely contribute to pollen maturation: PRX9 and PRX40. After further investigation, Jacobowitz determined that the two genes encode enzymes that work in conjunction with another type of protein called extensin and together they form the supportive walls that act like a scaffold in the tapetum.

Weng, who is also an assistant professor of biology at Massachusetts Institute of Technology, likens extensins to bricks in a wall and the PRX9 and PRX40 proteins to the mortar. Pushing against a wall can easily compromise its structure unless mortar bonds the bricks together. The same seems to be true with extensins and PRX9 and PRX40. The extensins and PRX9/PRX40 wall in the tapetum remained intact until Jacobowitz genetically “knocked out” the mortar genes. With the mortar gone, the scaffolding loses its integrity, and the tapetum collapses into the space where the pollen develops, either crushing or starving it. The result appears similar to what occurs in the tapetum of stressed wheat and rice plants, and the final effects are similar as well: Both the stressed crops and Arabidopsis lacking PRX9 and PRX40 are male sterile and do not produce pollen.

After further investigation, Jacobowitz and colleagues determined that the PRX9 and PRX40 genes are closely related and first appeared at pivotal moments in plant history. PRX40 is highly conserved among land plants and originated about 470 million years ago, when plants first emerged onto land from the seas and rivers. PRX9 seems to have evolved from PRX40 as a redundant backup when flowering plants diverged from nonflowering plants.

Pollen creation is a delicate process that plants have evolved over millions of years. Insights such as these into how plants maintain the integrity of their reproductive system are invaluable toward understanding how we might be able to generate crops capable of withstanding environmental stresses like heat and drought that could threaten our food supply.

This work was supported by Pew Scholars Program in the Biomedical Sciences (27345), the Searle Scholars Program (15-SSP-162), and the National Science Foundation (CHE-1709616 and 1122374).

Written by Nicole Giese Rura

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Jing-Ke Weng’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.

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Citation:

“PRX9 and PRX40 are extensin peroxidases essential for maintaining tapetum and microspore cell wall integrity during Arabidopsis anther development”

Plant Cell, online March 18, 2019, DOI: https://doi.org/10.1105/tpc.18.00907

Joseph R. Jacobowitz, William C. Doyle, and Jing-Ke Weng.

Biologists find a way to boost intestinal stem cell populations

Study suggests that stimulating stem cells may protect the gastrointestinal tract from age-related disease.

Anne Trafton | MIT News Office
March 28, 2019

Cells that line the intestinal tract are replaced every few days, a high rate of turnover that relies on a healthy population of intestinal stem cells. MIT and University of Tokyo biologists have now found that aging takes a toll on intestinal stem cells and may contribute to increased susceptibility to disorders of the gastrointestinal tract.

The researchers also showed that they could reverse this effect in aged mice by treating them with a compound that helps boost the population of intestinal stem cells. The findings suggest that this compound, which appears to stimulate a pathway that involves longevity-linked proteins known as sirtuins, could help protect the gut from age-related damage, the researchers say.

“One of the issues with aging is organ dysfunction, accompanied by a decline in the activity of the stem cells that nurture and replenish that organ, so this is a potentially very useful intervention point to either slow or reverse aging,” says Leonard Guarente, the Novartis Professor of Biology at MIT.

Guarente and Toshimasa Yamauchi, a professor at the University of Tokyo, are the senior authors of the study, which appears online in the journal Aging Cell on March 28. The lead author of the paper is Masaki Igarashi, a former MIT postdoc who is now at the University of Tokyo.

Population growth

Guarente’s lab has long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction.

In a paper published in 2016, Guarente and Igarashi found that in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In their new study, they set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals.

“That has real implications for health because just having more stem cells is all well and good, but it might not equate to anything in the real world,” Guarente says. “Knowing that the guts are actually more stress-resistant if they’re NR- supplemented is pretty interesting.”

Protective effects

Guarente says he believes that NR is likely acting through a pathway that his lab previously identified, in which boosting NAD turns on not only SIRT1 but another gene called mTORC1, which stimulates protein synthesis in cells and helps them to proliferate.

“What we would hypothesize is that the NAD replenishment in old mice is driving this pathway of growth that’s working through SIRT1 and TOR to reverse the decline that has occurred with aging,” he says.

The findings suggest that NAD might have a protective effect against diseases of the gut, such as colitis, in older people, he says. Guarente and his colleagues have previously found that NAD precursors can also stimulate the growth of blood vessels and muscles and boost endurance in aged mice, and a 2016 study from researchers in Switzerland found that boosting NAD can help replenish muscle stem cell populations in aged mice.

In 2014, Guarente started a company called Elysium Health, which sells a dietary supplement containing NR combined with another natural compound called pterostilbene, which is an activator of SIRT1.

The research was funded, in part, by the National Institutes of Health and the Glenn Foundation for Medical Research.

Start signal for sex cell creation
Greta Friar | Whitehead Institute
February 27, 2019

Cambridge, MA — Cells can divide and multiply in two ways: mitosis, in which the cell replicates itself, creating two copies identical to the original; or meiosis, in which the cell shuffles its DNA and divides twice, creating four genetically unique cells, each with half of the original cell’s number of chromosomes. In mammals, these latter cells become eggs and sperm.

How do germ line cells, the repository of cells that create eggs and sperm, know when to stop replicating themselves and undergo meiosis? Researchers had been aware that a protein called STRA8, which is only active in germ line cells, was involved in initiating meiosis, but they did not know how. New research from Whitehead Member and Institute Director David Page, also a professor of biology at Massachusetts Institute of Technology and an investigator with Howard Hughes Medical Institute; Mina Kojima, formerly a Massachusetts Institute of Technology graduate student and now a postdoctoral researcher at Yale; and visiting scientist Dirk de Rooij has revealed that in mice, STRA8 initiates meiosis by activating and amplifying a network of thousands of genes. This network includes genes involved in the early stages of meiosis, DNA replication, and other cell division processes. The research was published in eLife on February 27, 2019.

In the past, researchers have had difficulty collecting enough cells on the cusp of meiosis to investigate STRA8’s role. In mammals, germ line cells are inside the body, difficult to access, and they begin meiosis in staggered fashion so few cells are at the same stage during an extraction. Researchers in Page’s lab had previously come up with an approach to solve this problem using developmental synchronization, manipulating the cells’ exposure to the chemical that triggers their development in order to prompt all of the cells to begin meiosis simultaneously. Once the cells were synced up, first author Kojima could get a large enough sample to observe patterns in gene expression leading up to and during meiosis, and to figure out where STRA8 is binding.

She found that STRA8 binds to the regulatory portions of DNA called promoter regions, which initiate or increase transcription of adjacent genes, of most critical meiosis genes. With some exceptions, STRA8 does not switch genes from off to on. Rather, genes in the STRA8-regulated network are already expressed at low levels and STRA8 binding massively ramps up their production. The researchers posit that meiosis is then initiated once the genes reach a threshold of expression. This finding sheds light on instances in previous studies in which researchers found meiosis-related genes active in cells not yet undergoing meiosis.

The researchers were surprised to find that STRA8 also amplifies many genes involved in mitosis. However, they suggest that the meiosis-specific genes activated by STRA8 take precedence in determining which of the two cell-cycle processes the cell will undergo. STRA8 regulates certain critical genes, such as Meioc and Ythdc2, which help to establish a meiosis-specific cell-cycle program.

This research enriches our understanding of the process of sexual reproduction. Identifying the expansive STRA8-regulated network has elucidated the start of meiosis: the moment a cell commits to recombining and dividing, relinquishing its genetic identity for the chance to create something — or someone — new.

This work was supported by the National Science Foundation and the Howard Hughes Medical Institute.

 

Written by Greta Friar

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David Page’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute Investigator and a Professor of Biology at the Massachusetts Institute of Technology.

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Full citation:

“Amplification of a broad transcriptional program by a common factor triggers the meiotic cell cycle in mice”

eLife, February 27, 2019, https://doi.org/10.7554/eLife.43738

Mina L. Kojima (1,2), Dirk G. de Rooij (1), and David C. Page (1,2,3)

1. Whitehead Institute, 455 Main Street, Cambridge, MA 02142, USA

2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA

3. Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA 02142, USA