Research Area: Genetics

An eye for a mouth: How regenerating flatworms keep track of body parts

Graduate student Lauren Cote identifies genes directing regeneration

Justin Chen
November 16, 2017

An eye for a mouth: How regenerating flatworms keep track of body parts

Person with brown hair in pony tail sits in front of computer and microscope.

Graduate student Lauren Cote identifies genes directing regeneration

Justin Chen

 

Peering down through a microscope at a petri dish, Lauren Cote, a sixth-year graduate student, watches the tip of a worm’s tail. Alone in the petri dish, the brown globule of tissue is regenerating an entirely new digestive system, a brain, and a pair of eye spots. After just a few weeks, the animal — a quarter-inch-long ribbon of flesh capped by a triangular head — is complete again. Swimming through the dish, the worm’s grainy, mahogany body fades to a translucent gray-blue along the edges, stretching and contracting as if hinting at its malleability.

Many animals regenerate. Salamanders replace their tails while zebrafish regrow damaged heart muscle. Even humans can renew large parts of their livers. However, few creatures can regenerate like planarians, a class of flatworms found in fresh and salt water habitats around the world — and in the Reddien lab at the Whitehead Institute.

Because planarians are masters of regeneration, able to replace any body part and even create a new animal from small chunks of tissue, they have become a focus of intense study. By examining the flatworm species Schmidtea mediterranea, Cote and other members of the Reddien lab have uncovered the ways cells communicate after injury to coordinate regeneration. Their work provides insight into how the ability to regenerate evolved, and how the healing process works in a variety of animals, including humans.

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Although regeneration seems mysterious, researchers have simplified the feat into two steps. First, planarians create the raw material to make new body parts by stimulating a group of rapidly dividing cells, called stem cells, that are the source of all new tissue in the worm. Second, these new cells need instructions to know what kind of tissue to become. Cote’s goal is to demystify this second step by locating a grid of information, like latitude and longitude lines on a map, that helps planarians keep track of their body parts and sense what is missing.

Hands suctioning small, black dots from petri dish.
Few creatures can regenerate like planarians, a class of flatworms found in fresh and salt water habitats around the world.

“The animal could have lost just the tip of its head or entire left side of its body,” Cote says, “and somehow it regrows the precise anatomy needed to make a complete worm.”

Over the past few years, research in the Reddien lab has demonstrated that a network of muscle cells spread throughout the worm’s body guides regeneration. To accomplish this task, muscle cells rely on a group of genes called position control genes (PCGs) which, based on Cote’s model, are predicted to encode proteins involved in cell communication. Depending on what PCGs are activated or expressed, muscle cells would send out a unique combination of signaling molecules that determine which body parts, such as eyes, stomach, or tail, would form.

“We like to imagine that muscle cells function like satellites and beam down information,” Cote says. “This allows stem cells to know where they are and what new body part to become.”

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To systematically identify PCGs from the roughly 20,000 genes expressed in Schmidtea mediterranea, Cote worked in tandem with postdoctoral researcher Lucila Scimone in the Reddien lab to perform a two-part study. First they created maps of gene expression by examining individual muscle cells. After inventorying the genes each individual muscle cell expressed, they aggregated the data into a whole body map, showing gene activity across the entire worm. Some genes were expressed in all muscle cells, implying a general function such as controlling contraction and relaxation. In contrast, other genes were expressed in precise regions of the worm, like the head or midsection, suggesting that they could act as PCGs by defining the identity of each area.

In the second half of the study, Cote and Scimone used molecular techniques to disrupt the activity of potential PCGs. “We hypothesized that if a gene were needed to direct regeneration, the worm would still be able to renew itself without that gene’s activity,” Cote says, “but the animal would end up with an abnormal body.”

Indeed, Cote found that disrupting four genes in particular, encoding signaling molecules and receptor-like proteins, led to defective regeneration; worms either grew extra eyes on their head or grew extra feeding tubes sprouting out of their midsection like elongated suction cups.  Together these four genes, along with a few previously identified genes controlling head and tail regeneration, comprise a short but expanding list of PCGs controlling the location and identity of new tissues. As scientists begin to understand the molecular details of planarian regeneration, they will test whether similar genes are used by other animals and humans.

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Although a biologist now, Cote began her academic life focusing on mathematics. As an undergraduate math major at the University of Chicago, she studied branches of mathematics such as analysis, algebra, and algebraic topology, a discipline that describes the properties of multidimensional shapes. After a summer project, Cote realized that — while she enjoyed learning mathematics — she found the research far too abstract.

“I was having a mid-college crisis,” she recalls. “I wanted to study something more visual where you could actually see what is going on.” Following this urge, Cote began to work in a lab examining fly development during her junior year. “I remember watching sheets of cells on the outside of a fly embryo folding in on themselves and sliding under the surface away from view. It made me wonder how cells make decisions and choreograph their movements to build a body. That’s how I got interested in developmental biology.”

After graduating from the University of Chicago, Cote worked as a lab technician for two years. During this time, she realized that her background in math and ability to think logically was an asset. “Putting together a mathematical proof is similar to publishing a research paper,” she says. “In both cases you are piecing together smaller bits of evidence into a cohesive argument.”

A series of blobs with white, green, purple and yellow specs inside them.
Gene expression maps from the first half of Cote’s and Scimone’s study. The head of the worm faces the top of the screen while the tail of the worm faces the bottom of the screen. Each worm is marked by purple, yellow, and green dots indicating the expression of three different genes expressed in muscle cells. These colors show how genes are localized to different areas of the worm and could act as PCGs.  In the second half of the study, Cote and Scimone identified PCGs by using molecular techniques to disrupt gene activity and looking for worms that regenerated abnormal bodies.

Encouraged by her successful venture into biological research, Cote decided to pursue a PhD in biology. She learned about the Reddien lab while taking a genetics course during her first year at MIT. Like Cote, many members of this group have backgrounds in other areas of science — including computational biology, development, evolution, biochemistry, and immunology — which helps them examine planarian regeneration from many perspectives.

“They were beginning to put together a story linking muscle cells to regeneration that was really intriguing,” Cote says. “I also liked the challenge of working with planarians because they are a fairly new lab animal. We’re still developing a lot of research tools so there is room to be creative and ask fundamental questions.”

By following an initial strand of curiosity as an undergraduate and identifying PCGs as a graduate student, Cote has begun to decipher the molecular language of regeneration.  As scientists learn more about how planarians replace missing body parts, new areas of exploration open. One pressing question­ is how planarian regeneration compares to that of other animals. To pursue that mystery, Cote plans on studying another animal as a postdoctoral researcher and eventually starting her own laboratory.

“I still haven’t made up my mind, “she says, “but I’m considering a lot of possibilities such as crustaceans, sea squirts, zebrafish, and axolotls.” Regardless of her final choice, Cote will be investigating how cells — essentially fatty membranes encasing a slurry of water and proteins — manage to form complex and intricate structures. She will be pursuing the same questions that first captivated her as an undergraduate in Chicago. “How do cells make decisions? How do they know to become an eye or a stomach or a brain?” she asks. “There is a lot more that I want to understand.”

Photo credit: Raleigh McElvery
Pairing mismatch helps impaired fish RNA cleavage proceed swimmingly
December 21, 2017

Beyond tending to its multitudes of genetic, metabolic, and developmental processes, eukaryotic cells must additionally be vigilant against invasion by parasitic sequences such as viruses and transposons. RNA interference (RNAi) is a defense used by eukaryotic cells to protect themselves from such threats to their genomic harmony. Cellular RNAi components slice and destroy invading double-stranded RNA sequences and also help snip and process microRNAs, RNA sequences encoded by the genome that play key roles in gene regulation. An important process that occurs naturally in our cells, RNAi has also been harnessed by scientists as a tool to study gene function in common models such as worms, fruit flies, and mice. While many researchers have been using RNAi to tease apart gene function for over a decade, those using zebrafish, a powerful vertebrate model, have been forced to use other approaches because RNAi just did not seem to work well in these animals. Now, researchers at Whitehead Institute have uncovered how small changes in the fish Argonaute (Ago) protein, an RNA slicing protein, that happened in its lineage an estimated 300 million years ago greatly diminished the efficiency of RNAi in these animals, while another ancestral feature, in a critical pre-microRNA, was retained that enabled the microRNA to still be produced despite the fish’s impaired Ago protein.

In an article published December 21 in the journal Molecular Cell, graduate student Grace Chen, along with both Whitehead Member David Bartel, also a professor of biology at Massachusetts Institute of Technology (MIT) and investigator with the Howard Hughes Medical Institute, and Whitehead Member and MIT professor of biology Hazel Sive, describe their discovery of a roughly 300 million-year-old, two amino acid substitutions in the fish Ago protein. The substitution is present in the ancestor all teleost fish, the class of fish which includes not only zebrafish but also the vast majority of fish species spanning those populating the ocean, aquarium, and supermarket. These two changes reside in and near the protein’s catalytic site and greatly decrease the ability of the fish Ago to perform its RNA slicing function, offering an explanation for why RNAi has not been a useful tool in zebrafish.

Despite the zebrafish’s deficiencies in RNAi, it is still able to produce the microRNA miR-451, an important regulator of red blood cell maturation and the only microRNA processed by Ago (the rest are produced with another protein called Dicer). MicroRNAs are short stretches of RNA that can regulate gene expression by inhibiting translation of mRNA into a protein and directing the destruction of mRNA before it can be used to make more protein. Since Chen had discovered that zebrafish lack an efficient Ago protein, it was mysterious as to how are fish were able to produce Ago cleavage-dependent miR-451. The Ago protein must process miR-451 by slicing the sequence out of a longer strand of RNA that has folded up on itself, forming a hairpin structure. What they determined was that in the pre-miR-451 hairpin in zebrafish, at a critical position in the miRNA, they found a “G–G” pairing mismatch that actually appears to facilitate cleavage by the impaired zebrafish Ago. No mismatch, no efficient cleavage.

Exploring the effects of a seed sequence mismatch on Ago-catalyzed cleavage kinetics further, they then tested its ability to slice other bound transcripts. The researchers discovered that while, as might be expected, a G–G mismatch slows Ago binding, it significantly enhances both slicing efficiency as well as the release of the bound product, more than off-setting the slower binding reaction kinetics and suggesting that non- “Watson–Crick” base pairing creates an exceptionally favorable geometry for the cleavage and release parts of the reaction.

These findings offer interesting insights into how animals can survive and thrive without an efficient RNAi system and suggest how the Ago protein could be “repaired” in order to allow zebrafish researchers to use RNAi in their experiments. Restoring a function that a lineage hasn’t had for 300 million years might also fuel additional findings into how the teleost class has diverged over time.

Written by Lisa Girard
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David Bartel’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 professor of biology at Massachusetts Institute of Technology and investigator with the Howard Hughes Medical Institute.
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Paper cited:
Chen GR, Sive H, and Bartel DP. A Seed Mismatch Enhances Argonaute2-Catalyzed Cleavage and Partially Rescues Severely Impaired Cleavage Found in Fish. Molecular Cell, Dec 21 2017 DOI: 10.1016/j.molcel.2017.11.032.
Harnessing nature’s riches
December 19, 2017

Cambridge, MA – Researchers at Whitehead Institute have reconstructed the full suite of biochemical steps required to make salidroside, a plant-derived compound widely used in traditional medicine to combat depression and fatigue and boost immunity and memory. Their new study, which appears online this week in the journal Molecular Plant, resolves some long-standing questions about how this compound is manufactured by a type of high-altitude plant, known commonly as golden root. This work not only paves a path toward large-scale synthetic efforts—thereby protecting plants already in danger of extinction—but also provides a model for dissecting the biochemical synthesis of a host of natural products, which represent a treasure trove for modern medical discoveries.

“By cracking open the natural synthesis of this compound, known as salidroside, we have helped eliminate a major bottleneck in the broader development of plant-derived natural products into pharmaceuticals,” says Jing-Ke Weng, the senior author of the paper, a Member of Whitehead Institute, and an assistant professor of biology at Massachusetts Institute of Technology. “We simply can’t rely on the native plants as the sole sources of these biologically important molecules.”

Golden root, also called Tibetan ginseng, typically grows in high-altitude, arctic environments, such as Tibet. It is well known in Eastern cultures for its medicinal properties and produces a variety of chemical substances, particularly salidroside, which have garnered interest in the biomedical research community for their potential therapeutic effects.

“People have tried to farm golden root, but the medicinal value is much lower because the plants make much less salidroside when cultivated outside of their normal habitat,” says Weng.

That means collecting enough salidroside to fuel scientific studies is largely impossible, without risking the viability of these plants and their surroundings. So Weng and his team, including first author Michael Torrens-Spence, set out to find a better way. “If we can figure out how plants make these high-value natural products, then we can devise sustainable engineering approaches to recreate such molecules—we won’t have to destroy nature in order to harness its riches,” says Torrens-Spence, a postdoctoral researcher in Weng’s laboratory.

Torrens-Spence and his colleagues used a systematic multi-omics approach to characterize various tissues from a three-month-old, greenhouse-grown golden root plant. By correlating the active genes with the abundance of key metabolites between various tissue types, the researchers created a massive biochemical catalog of the plant’s tissues.

The researchers then mined these data and matched the likely biochemical precursors of salidroside with the candidate genes (and their corresponding enzymes) responsible for those compounds’ synthesis. This approach allowed Weng and his team to create a kind of draft blueprint of how salidroside is made in nature.

To test the validity of this draft blueprint—and the molecular players from the golden root plant that comprise it—the scientists turned to two well-studied laboratory organisms: the baker’s yeast Saccharomyces cerevisiae and the tobacco plant Nicotiana benthamiana. Normally, these organisms do not make salidroside. But if the researchers’ model was correct, by inserting the candidate genes involved in salidroside synthesis Weng and his colleagues should be able to bestow that special property upon them.

That is precisely what the researchers did. Using three key enzymes they identified through their “-omics” approach, including 4HPAAS (4-hydroxyphenylacetaldehyde synthase), 4HPAR (4-hydroxyphenylacetaldehyde reductase), and T8GT (tyrosol:UDP-glucose 8-O-glucosyltransferase), they engineered yeast and tobacco plants with the capacity to make salidroside. Notably, this biochemical pathway for synthesizing salidroside involves three enzymes, rather than four, as had previously been proposed.

“This is an exciting proof-of-principle for how we can systematically unlock the biochemistry behind a range of intriguing plant-derived natural products,” says Weng. “With this capability, we can accelerate biomedical studies of these unique compounds as well as their potential therapeutic development.”

Written by Nicole Davis
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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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Full citation:
“Complete pathway elucidation and heterologous reconstitution of Rhodiola salidroside biosynthesis”
Molecular Plant, online December 19, 2017. DOI: 10.1016/j.molp.2017.12.007
Michael P. Torrens-Spence (1), Tomáš Pluskal (1), Fu-Shuang Li (1), Valentina Carballo (1) and Jing-Ke Weng (1,2).
1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Small RNA mediates genetic parental conflict in seed endosperm
December 19, 2017

CAMBRIDGE, MA–When it comes to gene expression in the endosperm of seeds, gene provenance matters. In this specialized tissue, plants actively strive to keep the expression of genes inherited from the mother versus the father in balance, according to Whitehead Institute scientists.

The endosperm, the starchy part of a seed that envelopes and nourishes the developing embryo, comprises two-thirds of the calories in a typical human diet. It is the meat of a coconut and the sweet part of the corn on the cob we eat.  In a paper published online December 19 in the journal Cell Reports, Whitehead Member Mary Gehring, first author and former Gehring graduate student Robert Erdmann, and colleagues reveal that the endosperm is also the site where the plant must actively orchestrate a delicate balance between expression of genes inherited from the mother and those of the father.  If this critical balance errs toward one parent or the other, seeds can be too small or even abort.

Unlike most plant cells, which have two copies of the genome, cells within the endosperm have three copies: one inherited from the father, and two inherited from the mother. This ratio is established when a sperm cell in the fertilizing pollen grain fuses with the central cell associated with the egg cell in a flower’s ovule. Unlike most cells, the central cell has two nuclei, so when the sperm’s nucleus merges with the central cell, the resulting endosperm is triploid.

 The 2-to-1 ratio of maternal to paternal gene expression is crucial, and deviation can have dire consequences:  If maternal gene expression is too high, the seeds are too small; if paternal gene expression is too high, the seeds abort. Although plant biologists have known the importance of this ratio for seed viability, the balance was assumed to be passively maintained for the majority of genes.  Previously, Gehring determined that a subset of genes expressed in the endosperm are imprinted—their expression is inherited from their parent. But what about the remaining majority of the genome?

Now Gehring and colleagues have discovered a role for small RNAs—snippets of RNA that interfere with and can reduce gene expression—in actively maintaining this 2-to-1 balance in those genes that are not imprinted.  This the first time scientists have documented small RNAs maintaining such a ratio. Using Arabadopsis thaliana and Arabadopsis lyrata plants, Gehring and her lab determined that these small RNAs tamp down the expression of maternally inherited genes. When the enzyme that creates the small RNAs is mutated, fewer small RNAs are produced, and the plant’s carefully balanced gene expression is thrown off. The resulting seeds have excessive maternal gene expression. To understand the significance of this elevated maternal gene expression, Satyaki Rajavasireddy, a postdoctoral researcher in Gehring’s lab and an author of the Cell Reports paper, turned to plants with seeds that abort  because they have additional copies of paternal genes. When these plants with extra paternal DNA had their small-RNA-producing enzyme mutated, the outcome was striking: The seeds were rescued and developed to maturity.

Although the research analyzed this phenomenon in A. thaliana and A. lyrata, Gehring expects it to be a widespread manifestation of the tug-of-war between maternal and paternal genetic contributions.

“Maintaining this maternal/paternal balance is crucial for seed development, including in crop plants,” says Gehring, who is also an associate professor of biology at Massachusetts Institute of Technology.  “We’ve looked at two species that are separated by 10 million years of evolution, and I anticipate we will find this mechanism in other species as well.”

This work was supported by the National Science Foundation (NSF CAREER grant 1453459).

Written by Nicole Giese Rura
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Mary Gehring’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also an associate professor of biology at Massachusetts Institute of Technology.
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Full Citation:
“A small RNA pathway mediates allelic dosage in endosperm”
Cell Reports, online December 19, 2017.
Robert M. Erdmann (1,2), P.R. V. Satyaki (1), Maja Klosinska (1), Mary Gehring (1,2).
1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142 USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
Epigenetic rheostat helps uncover how gene regulation is inherited and maintained
December 14, 2017

While our genome contains a vast repertoire of genes that are responsible for virtually all of the cellular and developmental processes life requires, it is the complex dance of regulating their expression that is vital for genetic programs to be executed successfully. Genes must be turned on and off at appropriate times or, in some cases, never turned on or off at all.

Methylation—the addition of chemical tags to DNA—typically reduces the expression of methylated genes. In many cases, DNA methylation can be thought of as roadblocks on a gene. The more methylated a gene is, the less likely it is that it will be active. Such genetic demarcations are critical to ensure that genes involved in particular stages of development are active at the right time, for example. Methylation is essential for proper cellular function, and its dysregulation is associated with diseases, such as cancer in humans. Despite its importance, little is known about how critical methylation patterns are inherited or maintained. Whitehead Institute Member Mary Gehring and her lab have identified a mechanism important for maintaining methylation, that when disrupted, results in the demethylation of large sections of the Arabidopsis plant’s genome. Their work is described this week in the journal Nature Communications.

Using an unusual gene in the plant Arabidopsis, Gehring is teasing apart the mechanisms that underpin methylation. By breaking this unique gene’s “circuit,” Gehring and Ben Williams, a postdoctoral researcher in her lab, have gained important insights into how methylation is maintained, including a surprising finding that previously erased methylation can be restored under certain circumstances.

In order to better understand methylation’s heritability, Gehring and Williams looked closely at an anomaly, the ROS1 gene in Arabidopsis plants, which encodes a protein that removes methylation from its own gene as well as others. Previously, Gehring and Williams had determined that ROS1 methylation actually functions in the complete opposite way from the existing paradigm—unlike most genes, when a short section of this gene is methylated, the gene is actually activated instead of inactivated. Conversely, if it is methylated, the gene is turned on. As a result, ROS1 can act as a rheostat for the Arabidopsis genome: As methylation increases, ROS1 turns on and begins removing methyl groups, and as methylation decreases, ROS1 shuts off and reduces its demethylating activity.

In the current research, Williams altered methylation at ROS1 so that its activity was uncoupled from methylation levels in the genome, in order to see what effects such a change would have on methylation throughout the entire genome. When he analyzed the plants’ methylation, it was haywire. Methylation was lost throughout the genome and progressively decreased in subsequent generations, except in a particular part of the genome called the heterochromatin—genomic areas that are strongly repressed. Interestingly, Williams found that, despite the alteration of the ROS1regulatory circuit, these heterochromatic sections of the genome actually regain their methylation and approach full methylation by the fourth generation— the same time point by which the rest of the genome has lost much of its methylation .

The researchers determined that the ROS1 circuit they uncovered is important for methylation homeostasis because it causes heritable loss of methylation when disrupted.  And yet methylation returns at some locations, albeit not immediately, suggesting that Arabidopsis enlists multiple mechanisms to maintain methylation homeostasis. Gehring and Williams are intrigued by that delay in remethylation and are working to identify its cause as well as other mechanisms that may also be at work regulating this critical process.

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (R01GM112851).

Written by Nicole Giese Rura
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Mary Gehring’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also an associate professor of biology at Massachusetts Institute of Technology.
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Full Citation:
“Stable transgenerational epigenetic inheritance requires a DNA methylation-sensing circuit”
Nature Communications, December 14, 2017.
Ben P. Williams (1) and Mary Gehring (1,2).
1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
Chris A. Kaiser

Education

  • PhD, 1987, MIT

Research Summary

The Kaiser lab studied protein folding and intracellular trafficking in the yeast S. cerevisiae. Their work focused on the protein folding in the endoplasmic reticulum (ER), quality control mechanisms in the ER, and membrane protein sorting in Golgi compartments. They combined genetic, biochemical, and cell biological methods to gain an understanding of the molecular mechanisms underlying each of these processes. Chris Kaiser is no longer accepting students.

Michael T. Hemann

Education

  • PhD, 2001, Johns Hopkins University
  • BS, 1993, Molecular Biology and Biochemistry, Wesleyan University

Research Summary

Many human cancers do not respond to chemotherapy, and often times those that initially respond eventually acquire drug resistance. Our lab uses high-throughput screening technology — combined with murine stem reconstitution and tumor transplantation systems — to investigate the genetic basis for this resistance. Our goal is to identify novel cancer drug targets, as well as strategies for tailoring existing cancer therapies to target the vulnerabilities associated with specific malignancies.

Rethinking transcription factors and gene expression

Study shows that, like proteins, genomes must fold appropriately to function properly and that some transcription factors provide the structural support.

Nicole Giese Rura | Whitehead Institute
December 7, 2017

Transcription — the reading of a segment of DNA into an RNA template for protein synthesis — is fundamental for nearly all cellular processes, including growth, responding to stimuli, and reproduction. Now, Whitehead Institute researchers have upended our understanding of how transcription is controlled and the role of transcription factors in the process.

The paradigm shift, described in an article online on Dec. 7 in the journal Cell, hinges on a small protein that plays a key role in genome structure and gives us new insights into how changes in the control of transcription and gene expression can lead to disease.

Transcription has several important players that must all be in the right place at the right time: the transcription machinery, transcription factors, promoters, and enhancers.  According to the existing model, transcription factors are proteins that bind to enhancer regions of the genome and recruit the transcription machinery to the promoter DNA regions, which then initiate the genes’ transcription.

“We’ve always assumed that the role of transcription factors was to recruit the transcription machinery to genes to turn them on or turn them off,” says Richard Young, a Whitehead Insistute member and professor of biology at MIT. “But we never imagined that the transcription factors we’ve studied for three decades actually contribute to the genome’s structure. And as a consequence, they regulate genes. So we now look at genomes like proteins: They have to fold up appropriately in order to control genes.”

Scientists have known that the genome’s structure — how it bends and folds — is essential for efficiently compressing two meters of DNA into each human cell, which is the equivalent of packing a strand ten football fields long into a space the size of a marble. Yet until recently, researchers have not had the tools necessary to appreciate this architecture’s importance in fine control of gene expression or study the genome’s structure at sites ready for transcription.

In 2014, Young and his lab determined that portions of the genome reside in loop-based structures, creating insulated neighborhoods that bring enhancers, promoters, and genes into close proximity. Each loop is tied at the top by a pair of molecules, called CTCF, that are bound together. This structure is essential for proper gene control: If the loop structure is broken, gene expression is altered, and cells can become diseased or die.

In the current research, Young along with co-first authors Abraham Weintraub and Charles Li took a closer look at a protein that is well known but not well understood: Yin Yang 1 (YY1). Hundreds of scientific papers have linked YY1 dysfunction to diseases such as viral infections, cancer, and arthritis, and yet the studies produced seemingly contradictory observations of YY1’s function.

According to Young and colleagues, YY1 is a unique transcription factor that occupies both enhancers and promoters, is essential for cell survival, and is found in almost every cell type in humans and mice. Like CTCF, YY1 can also pair with itself and bind to DNA to form loops that enhance DNA transcription.

“YY1 is expressed broadly, and it is necessary for establishing enhancer-promoter loops in multiple cell types,” says Weintraub. “That’s its job, not recruiting the transcription apparatus. When the structure created by YY1 is removed, the genome is no longer folded properly, gene control is lost and transcription of the affected genes is significantly diminished, which can cause dysfunction.”

This model of YY1’s function could account for its association with a number of disparate diseases. Earlier this year, scientists reported YY1 syndrome — a genetic syndrome causing cognitive disabilities in people with mutations in their YY1 gene.

According to Young, YY1 is probably not the only transcription factor with this loop-forming role, and his lab will be searching for additional factors with similar functions.

“YY1 is most likely just the first one, and there are probably a bunch of collaborators that have similar roles,” says Young. “Instead of the classic function that we thought these transcription factors had — interacting with the transcription apparatus and giving instructions on how much or how little of a gene’s transcript to produce — they are bringing together regulatory elements with the gene. The whole job of these transcription factors is just making structure. We are realizing that the things that form physical structures are much more important than we had appreciated.”

The researchers’ work was supported by the National Institutes of Health, the Ludwig Graduate Fellowship funds, the National Science Foundation, the American Cancer Society, a Margaret and Herman Sokol Postdoctoral Award, the Damon Runyon Cancer Research Foundation, and the Cancer Research Institute. The Whitehead Institute has filed a patent application based on this study.

Michael T. Laub

Education

  • PhD, 2002, Stanford University
  • BS, 1997, Molecular Biology, University of California, San Diego

Research Summary

We study the biological mechanisms and evolution of how cells process information to regulate their own growth and proliferation. Using bacteria as a model organism, we aim to elucidate the detailed molecular basis for this remarkable regulatory capability, and understand the selective pressures and mechanisms that drive the evolution of signaling pathways. Our work is rooted in a desire to develop a deeper, fundamental understanding of how cells function and evolve, but it also has important medical implications since many signaling pathways in pathogenic bacteria are needed for virulence.

Awards

  • Howard Hughes Medical Institute, HHMI Investigator, 2015
  • National Science Foundation, Presidential Early Career Award for Scientists and Engineers, 2010
  • Howard Hughes Medical Institute, Early Career Scientist, 2009
Anthony J. Sinskey

Education

  • ScD, 1966, Massachusetts Institute of Technology
  • BS, 1962, Food Science, University of Illinois, Urbana-Champaign

Research Summary

The Sinskey Lab leverages an interdisciplinary approach to metabolic engineering — focusing on the fundamental physiology, biochemistry, and molecular genetics of important organisms to determine key factors that regulate the synthesis of different biomolecules. The lab supports a broad range of interests, examining amino acid metabolism in Corynebacterium glutamicum, bioremediation and bioconversion processes in Rhodococcus, and biopolymer synthesis in Gram-negative bacteria. As for eukaryotic systems, we study both lipid biosynthesis and embryogensis in oil palm, as well as the accumulation of secondary metabolites in tropical plants.