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.

Laurie A. Boyer

Education

  • PhD, 2001, University of Massachusetts Medical School
  • BS, 1990, Biomedical Science, Framingham State University

Research Summary

We investigate how complex circuits of genes are regulated to produce robust developmental outcomes particularly during heart development. A main focus is to determine how DNA is packaged into chromatin, and how ATP-dependent chromatin remodelers modify this packaging to control lineage commitment. We are now applying these principles to develop methods to stimulate repair of damaged cardiac tissue (e.g., regeneration). Our ability to combine genomic, genetic, biochemical, and cell biological approaches both in vitro and in vivo as well as ongoing efforts to use tissue engineering to model the 3D architecture of the heart will ultimately allow us to gain a systems level and quantitative understanding of the regulatory circuits that promote normal heart development and how faulty regulation can lead to disease.

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Awards

  • Medicine by Design Distinguished Lecture, 2017
  • Cardiovascular Rising Star Distinguished Lecture, 2017
  • American Heart Association Innovative Research Award, 2013
  • Irvin and Helen Sizer Career Development Award, 2012
  • Smith Family Award for Excellence in Biomedical Science, 2009
  • Massachusetts Life Sciences Center New Investigator Award, 2008
  • Pew Scholars Award in the Biomedical Sciences, 2008
  • Honorary Doctorate, Framingham State College, 2007
  • The Scientific American World’s 50 Top Leaders in Research, Business or Policy, 2006
Michael B. Yaffe

Education

  • PhD, 1987, Case Western Reserve University; MD, 1989, Case Western Reserve University
  • BS, 1981, Chemistry with Concentration in Solid-State and Polymer Physics, Cornell University

Research Summary

Our goal is to understand how signaling pathways are integrated at the molecular and systems levels to control cellular responses. We have two main focuses: First, we study signaling pathways and networks that control cell cycle progression and DNA damage responses in cancer and cancer therapy. Second, we examine the cross-talk between inflammation, cytokine signaling and cancer. Much of our work focuses on how modular protein domains and kinases work together to build molecular signaling circuits, and how this information can be used to design synergistic drug combinations for the personalized treatment of human disease.

Awards

  • MacVicar Faculty Fellow, 2021
  • Fellow, Association of American Physicians, 2021
  • Teaching with Digital Technology Award, 2018
Amy E. Keating

Education

  • PhD, 1998, University of California, Los Angeles
  • SB, 1992, Physics, Harvard University

Research Summary

Our goal is to understand, at a high level of detail, how the interaction properties of proteins are encoded in their sequences and structures. We investigate protein-protein interactions by integrating data from high throughput assays, structural modeling, and bioinformatics with biochemical and biophysical experiments. Much of our work focuses on α-helical coiled-coil proteins, Bcl-2 apoptosis-regulating proteins, and protein domains that bind to short linear motifs.

Monty Krieger

Education

  • PhD, 1976, California Institute of Technology
  • BS, 1971, Chemistry, Tulane University

Research Summary

We use genetic, biochemical, physiologic, chemical, cellular and molecular biological methods to study cell surface receptor structure and function. We focus on lipoprotein receptors — in particular, the High Density Lipoprotein (HDL) receptor called Scavenger Receptor, Class B, Type I (SR-BI). Our analyses have provided insight into basic biological processes, contributed to our understanding of atherosclerosis and coronary heart disease (CHD) and have uncovered an unexpected connection between cholesterol and mammalian female infertility.

Awards 

  • Tulane University School of Science and Engineering Outstanding Alumnus Award, 2010
  • National Academy of Sciences, Member, 2009
  • Outstanding Achievement Award for Contributions to Atherosclerosis Research, International Atherosclerosis Society, 2009
  • Margaret MacVicar Faculty Fellow, 1993-2003
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
Gene-Wei Li

Education

  • PhD, 2010, Harvard University
  • SB, 2004, Physics, National Tsinghua University

Research Summary

We seek to understand the optimization of bacterial proteomes at both mechanistic and systems levels. Our work combines high-precision assays, genome-wide measurements, and quantitative/biophysical modeling. Ongoing projects focus on the design principles of transcription, translation, and RNA maturation machineries in the face of competing cellular processes.

Awards

  • Smith Odyssey Award, 2020
  • MIT Committed to Caring Award, 2020
  • NSF Career Award, 2019
  • Pew Biomedical Scholar, 2017
  • Smith Family Award for Excellence in Biomedical Research, 2017
  • NIGMS R35 Maximizing Investigator Research Award, 2017
  • Sloan Research Fellowship, 2016
  • Searle Scholar, 2016
  • NIH Pathway to Independence Award, 2013
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.

Graham C. Walker

Education

  • PhD, 1974, University of Illinois
  • BS, 1970, Chemistry, Carleton University

Research Summary

Our research is concentrated in two major areas. First, we aim to understand how the proteins involved in DNA repair, mutagenesis and other cellular responses to DNA damage are regulated. Some of our discoveries have the potential to improve chemotherapy. Second, we probe how nitrogen-fixing nodules develop on legumes, and the relationship between rhizobial functions required for nodule invasion/infection and mammalian pathogenesis.

Awards

  • Revolutionizing Innovative, Visionary Environmental health Research (RIVER), R35 Outstanding Investigator Award, 2017
  • National Academy of Sciences, Member, 2013
  • Howard Hughes Medical Institute, HHMI Professor, 2010
  • University of Guelph, Doctor of Science, honoris causa, 2010
  • American Association for the Advancement of Science, Fellow, 2008
  • Environmental Mutagen Society, EMS Award, 2006
  • American Academy of Arts and Sciences, Fellow, 2004
  • American Cancer Society, Research Professor, 2002
  • Howard Hughes Medical Institute, HHMI Professor, 2002
  • Charles Ross Scholar, 2000-2003
  • American Academy of Microbiology, Fellow, 1994
  • Margaret MacVicar Faculty Fellow, 1992-2002
  • John Simon Guggenheim Memorial Foundation, Guggenheim Fellowship, 1984
  • Massachusetts Institute of Technology, MacVicar Faulty Fellow, 1984
  • Rita Allen Foundation, Career Development Award, 1978
Robert T. Sauer

Education

  • PhD, 1979, Harvard University
  • BA, 1972, Biophysics, Amherst College

Research Summary

We study the relationship between protein structure, function, sequence and folding. We focus on the molecular machines that degrade or remodel proteins, targeting proteins for these ATP-dependent reactions. Our experimental tools include biochemistry and single-molecule biophysics, structural biology, protein design and engineering, and molecular genetics.

Awards

  • Protein Society, Stein and Moore Award, 2013
  • Protein Society, Hans Neurath Award, 2007
  • Protein Society, Amgen Award, 2001
  • National Academy of Sciences, Member, 1996
  • American Academy of Arts and Sciences, Fellow, 1993