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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
Jacqueline Lees

Education

  • PhD, 1990, University of London
  • BSc, 1986, Biochemistry, University of York

Research Summary

We identify the proteins and pathways involved in tumorigenicity — establishing their mechanism of action in both normal and tumor cells. To do so, we use a combination of molecular and cellular analyses, mutant mouse models and genetic screens in zebrafish.

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.

Tania A. Baker

Education

  • PhD, 1988, Stanford University
  • BS, 1983, Biochemistry, University of Wisconsin-Madison

Research Summary

Our goal is to understand the mechanisms and regulation behind AAA+ unfoldases and macromolecular machines from the “Clp/Hsp100 family” of protein unfolding enzymes. We study these biological catalysts using biochemistry, structural biology, molecular biology, genetics, and single molecule biophysics.

No longer accepting students.

Awards

  • Margaret MacVicar Faculty Fellow, 2008-2018
  • National Academy of Sciences, Member, 2007
  • American Academy of Arts and Sciences, Fellow, 2005
  • Howard Hughes Medical Institute, HHMI Investigator, 1994
Celebrating a decade of interdisciplinary microbiology

The Microbiology Graduate PhD Program spans 50 labs across 10 departments and divisions, offering a broad approach to microbial science and engineering.

Raleigh McElvery | Department of Biology
December 12, 2017

Ten years ago, MIT launched the Microbiology Graduate PhD Program. Today, it boasts 28 alumni and 33 current students, and offers a broad, interdisciplinary approach to microbial science and engineering. Between five and eight trainees enroll each year and can choose among more than 50 labs spanning 10 departments and divisions — from biology and biological engineering to chemical engineering and physics.

Many diverse disciplines are rooted in microbiology. Basic scientists use microorganisms as model systems to understand fundamental biological processes. Engineers leverage microorganisms to create new manufacturing processes and energy sources. Even ecologists, biomedical researchers, and earth scientists dedicate their careers to investigating the role of microbes in our ecosystems, on our bodies, and on our planet. In sum, the study of microbiology permeates so many research areas that no single department at MIT could house them all.

The idea for an interdisciplinary microbiology program first came to Alan Grossman, head of the Department of Biology, while he was recovering from a heart transplant back in 2006.

“There were people scattered all over MIT who were doing microbial science and engineering, but there was no mechanism to connect them or give students outside those departments easy access to the labs,” Grossman says. “I began by talking to a few faculty members in order to gauge general interest, before pitching it to a handful of department heads and forming a committee. Everyone was very excited about it, and it really grew from the ground up.”

The Committee on Graduate Programs approved his proposal in May 2007, and the first cohort of eight students began in the fall of 2008. Martin Polz, co-director since 2015 and professor of civil and environmental engineering, sat on Grossman’s initial committee.

“MIT’s program is unique from most other microbiology programs because it’s so interdisciplinary,” Polz says. “Many microbiology programs across the country are associated with medical schools and focused primarily on pathogenesis. The students who apply here really appreciate the breadth of our program, and it has become a fixture at MIT over the years.”

Kristala Prather, co-director since 2013 and professor of chemical engineering, said the program also provides an opportunity to bring life scientists and engineers together to tackle research questions.

“I find there is a difference in the way engineers and scientists approach research problems,” Prather says. “Each approach has rigor, but having both perspectives breeds a richer set of discussions than just hearing from one discipline alone.”

During the past 10 years, Prather has watched a thriving and diverse community unite, spurred by a common interest in the microbial world.

Nathaniel Chu, who matriculated in 2014, said the program allows him to sample different disciplines while still maintaining a close affiliation with his advisor’s home department, Biological Engineering. As part of Eric Alm’s lab, Chu studies the interaction between the gut microbiome and immune system, and how imbalances in that delicate relationship can trigger conditions such as Type 2 diabetes, obesity, and inflammatory bowel disease.

“The program provides flexibility to explore your research interests, and my advisor has given me a lot of space to conceive and manage my own projects,” Chu says. “I’ve been able to interact with a diverse set of individuals within the microbiology circle, including clinical partners, immunologists, geneticists, bioinformaticians, and computational biologists.”

Jacquin Niles, incoming co-director, was a junior faculty member in Department of Biological Engineering when Grossman first proposed the idea. He says the students — past and present — are the heart of the program.

“A lot has changed over the 10 years the program has been in existence, but the caliber of students has remained consistent,” Niles says. “If I had to emphasize any particular aspect of the program, the students would be numbers one, two, and three. Each generation has been exceptional, and they are all very much on top of their research game.”

Michael Laub, co-director from 2012 to 2015 and professor of biology, adds that the early students deserve much credit for the program’s success. “They took a chance on a brand-new initiative, and as a result we ended up attracting ambitious, risk-taking, and creative folks who really paved the way for current students,” he says.

Alumni pursue a variety of careers, ranging from academia to industry. Some join existing institutions or companies. Others start their own.

Mark Smith PhD ’14 was a member of the second graduating class. Like Chu, he was one of Alm’s advisees, studying networks of gene exchange within the human microbiome, and building statistical models to determine the role of environment in various gut-related diseases. Smith went on to co-found a nonprofit organization known as OpenBiome, harnessing the microbiome to cure recurrent Clostridium difficile infections. In 2016, he co-founded another company, Finch Therapeutics Group, focused on scaling and commercializing clinical treatments for diseases rooted in the microbiome. In 2017, he was named to the Forbes 30 Under 30 list for science.

“OpenBiome and Finch Therapeutics were really a translation of the initial work that was done through the microbiology program, and a step toward developing those tools to improve human health,” Smith says. “The program taught me the foundational work I’ve come to rely on in almost every aspect of my job today.”

Like Smith, Jacob Rubens PhD ’16 aims to apply his training at MIT to help develop new products. After working in Timothy Lu’s lab — straddling the realms of biological engineering and electrical engineering — Rubens joined Flagship Pioneering, a company that starts, funds, and runs breakthrough biotechnology startups in Cambridge, Massachusetts. Rubens was also named to the Forbes 30 Under 30 list for science in 2017.

During the six years that Rubens was at MIT, he watched the microbiology cohort grow from roughly 20 to a force permeating more labs across campus than he could count.

“It’s heartwarming to see people bringing a microbiological perspective into all these different spaces, and influencing cutting-edge research across the Institute,” he says. “As a microbiology student, you become an integrator and synthesizer of many different viewpoints, and a node to foster cross-talk between disciplines.”

As Niles prepares to assume the role of co-director in July 2018 and usher in the program’s second decade, he intends to maintain its integrity and structure.

“The program has matured into what it is today thanks to a lot of previous, careful thought,” he says. “The students have indicated that there is a lot of value in the structure that we’ve refined over the years, and so my goal is to continue that positive momentum.”

Douglas Lauffenburger

Education

  • PhD, 1979, University of Minnesota
  • BS, 1975, Chemical Engineering, University of Illinois, Urbana-Champaign

Research Summary

The Lauffenburger laboratory emphasizes integration of experimental and mathematical/computational analysis approaches, toward development and validation of predictive models for physiologically-relevant behavior in terms of underlying molecular and molecular network properties. Our work has been recognized as providing contributions fostering the interface of bioengineering, quantitative cell biology, and systems biology. Our main focus has been on fundamental aspects of cell dysregulation, complemented by translational efforts in identifying and testing new therapeutic ideas. Applications addressed have chiefly resided in various types of cancer (including breast, colon, lung, and pancreatic cancers along with leukemias and lymphomas), inflammatory pathologies (such as endometriosis, Crohn’s disease, colitis, rheumatoid arthritis, and Alzheimer’s disease), and the immune system (mainly for vaccines against pathogens such as HIV, malaria, and tuberculosis). We have increasingly emphasized complex tissue contexts, including mouse models, human subjects, and tissue-engineered micro-physiological systems platforms in association with outstanding collaborators. From our laboratory have come more than 100 doctoral and postdoctoral trainees. Many hold faculty positions at academic institutions in the USA, Canada, and Europe; others have gone on to research positions in biotechnology and pharmaceutical companies; and others yet have moved into policy and government agency careers.

Awards

  • Bernard M. Gordon Prize for Innovation in Engineering and Technology Education, National Academy of Engineering, 2021
  • American Association for the Advancement of Science, Member, 2019
  • American Academy of Arts and Sciences, Fellow, 2001
  • John Simon Guggenheim Memorial Foundation, Guggenheim Fellowship, 1989
Matthew Vander Heiden

Education

  • PhD, 2000, University of Chicago; MD, 2002, University of Chicago
  • SB, 1994, Biological Chemistry, University of Chicago

Research Summary

We study the biochemical pathways cells use and how they are regulated to meet the metabolic requirements of cells in different physiological situations. We focus on the role of metabolism in cancer, particularly how metabolic pathways support cell proliferation. We aim to translate our understanding of cancer cell metabolism into novel cancer therapies.

Awards

  • National Academy of Medicine, 2024
  • Howard Hughes Medical Institute Faculty Scholar, 2016
  • SU2C Innovative Research Grant Recipient, 2016
Researchers establish long-sought source of ocean methane

An abundant enzyme in marine microbes may be responsible for production of the greenhouse gas.

Anne Trafton | MIT News Office
December 7, 2017

Industrial and agricultural activities produce large amounts of methane, a greenhouse gas that contributes to global warming. Many bacteria also produce methane as a byproduct of their metabolism. Some of this naturally released methane comes from the ocean, a phenomenon that has long puzzled scientists because there are no known methane-producing organisms living near the ocean’s surface.

A team of researchers from MIT and the University of Illinois at Urbana-Champaign has made a discovery that could help to answer this “ocean methane paradox.” First, they identified the structure of an enzyme that can produce a compound that is known to be converted to methane. Then, they used that information to show that this enzyme exists in some of the most abundant marine microbes. They believe that this compound is likely the source of methane gas being released into the atmosphere above the ocean.

Ocean-produced methane represents around 4 percent of the total that’s discharged into the atmosphere, and a better understanding of where this methane is coming from could help scientists better account for its role in climate change, the researchers say.

“Understanding the global carbon cycle is really important, especially when talking about climate change,” says Catherine Drennan, an MIT professor of chemistry and biology and Howard Hughes Medical Institute Investigator. “Where is methane really coming from? How is it being used? Understanding nature’s flux is important information to have in all of those discussions.”

Drennan and Wilfred van der Donk, a professor of chemistry at the University of Illinois at Urbana-Champaign, are the senior authors of the paper, which appears in the Dec. 7 online edition of Science. Lead authors are David Born, a graduate student at MIT and Harvard University, and Emily Ulrich, a graduate student at the University of Illinois at Urbana-Champaign.

Solving the mystery

Many bacteria produce methane as a byproduct of their metabolism, but most of these bacteria live in oxygen-poor environments such as the deep ocean or the digestive tract of animals — not near the ocean’s surface.

Several years ago, van der Donk and University of Illinois colleague William Metcalf found a possible clue to the mystery of ocean methane: They discovered a microbial enzyme that produces a compound called methylphosphonate, which can become methane when a phosphate molecule is cleaved from it. This enzyme was found in a microbe called Nitrosopumilus maritimus, which lives near the ocean surface, but the enzyme was not readily identified in other ocean microbes as one would have expected it to be.

Van der Donk’s team knew the genetic sequence of the enzyme, known as methylphosphonate synthase (MPnS), which allowed them to search for other versions of it in the genomes of other microbes. However, every time they found a potential match, the enzyme turned out to be a related enzyme called hydroxyethylphosphonate dioxygenase (HEPD), which generates a product that is very similar to methylphosphonate but cannot be cleaved to produce methane.

Van der Donk asked Drennan, an expert in determining chemical structures of proteins, if she could try to reveal the structure of MPnS, in hopes that it would help them find more variants of the enzyme in other bacteria.

To find the structure, the MIT team used X-ray crystallography, which they performed in a special chamber with no oxygen. They knew that the enzyme requires oxygen to catalyze the production of methylphosphonate, so by eliminating oxygen they were able to get snapshots of the enzyme as it bound to the necessary reaction partners but before it performed the reaction.

The researchers compared the crystallography data from MPnS with the related HEPD enzyme and found one small but critical difference. In the active site of both enzymes (the part of the protein that catalyzes chemical reactions), there is an amino acid called glutamine. In MPnS, this glutamine molecule binds to iron, a necessary cofactor for the production of methylphosphonate. The glutamine is fixed in an iron-binding orientation by the bulky amino acid isoleucine, which is directly below the glutamine in MPnS. However, in HEPD, the isoleucine is replaced by glycine, and the glutamine is free to rearrange so that it is no longer bound to iron.

“We were looking for differences that would lead to different products, and that was the only difference that we saw,” Born says. Furthermore, the researchers found that changing the glycine in HEPD to isoleucine was sufficient to convert the enzyme to an MPnS.

An abundant enzyme

By searching databases of genetic sequences from thousands of microbes, the researchers found hundreds of enzymes with the same structural configuration seen in their original MPnS enzyme. Furthermore, all of these were found in microbes that live in the ocean, and one was found in a strain of an extremely abundant ocean microbe known as Pelagibacter ubique.

“This exciting result builds on previous, related studies showing that the metabolism of the methylphosphonate can lead to the formation of methane in the oxygenated ocean. Since methane is a potent greenhouse gas with poorly understood sources and sinks in the surface ocean, the results of this study will serve to facilitate a more comprehensive understanding of the methylphosphonate cycle in nature,” says David Karl, a professor of oceanography at the University of Hawaii, who was not involved in the research.

It is still unknown what function the MPnS enzyme and its product serve in ocean bacteria. Methylphosphonates are believed to be incorporated into fatty molecules called phosphonolipids, which are similar to the phospholipids that make up cell membranes.

“The function of these phosphonolipids is not well-established, although they’ve been known to be around for decades. That’s a really interesting question to ask,” Born says. “Now we know they’re being produced in large quantities, especially in the ocean, but we don’t actually know what they do or how they benefit the organism at all.”

Another key question is how the production of methane by these organisms is influenced by environmental conditions in the ocean, including temperature and pollution such as fertilizer runoff.

“We know that methylphosphonate cleavage occurs when microbes are starved for phosphorus, but we need to figure out what nutrients are connected to this, and how is that connected to the pH of the ocean, and how is it connected to temperature of the ocean,” Drennan says. “We need all of that information to be able to think about what we’re doing, so we can make intelligent decisions about protecting the oceans.”

The research was funded by the National Institutes of Health and the Howard Hughes Medical Institute.

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.

Richard O. Hynes

Education

  • PhD, 1971, MIT
  • MA, 1970, Biochemistry, Cambridge University
  • BA, 1966, Biochemistry, Cambridge University

Research Summary

We study the mechanisms underlying the spread of tumor cells throughout the body, known as metastasis. We are particularly interested in the role of the extracellular matrix — a fibrillar meshwork of proteins that surrounds both normal and tumor cells, which plays many important roles in tumor progression. We also investigate changes in the metastatic cells themselves and in the contributions of normal cells, both in terms of metastasis and other bodily functions.

Awards

  • Paget-Ewing Award, Metastasis Research Society, 2018
  • Inaugural American Society for Cell Biology (ASCB) Fellow, 2016
  • American Association for Cancer Research (AACR) Academy, Fellow, 2014
  • Distinguished Investigator Award, International Society for Matrix Biology, 2012
  • Earl Benditt Award, North American Vascular Biology Organization, 2010
  • Robert and Claire Pasarow Medical Research Award – Cardiovascular, 2008
  • E.B. Wilson Medal, American Society for Cell Biology, 2007
  • President, American Society for Cell Biology, 2000
  • Gairdner Foundation International Award, 1997
  • National Academy of Sciences, Member, 1996
  • National Academy of Medicine, Member, 1995
  • Royal Society of London, Fellow, 1989
  • Howard Hughes Medical Institute, HHMI Investigator, 1988
  • American Association for the Advancement of Science, Fellow, 1987
  • American Academy of Arts and Sciences, Fellow, 1987
  • John Simon Guggenheim Memorial Foundation, Guggenheim Fellowship, 1982

Media Inquiries

For media inquiries, please email rhynes-admin@mit.edu.