Center for Epigenetics and Metabolism 2024 Symposium

Edith Heard, PhD, FRS
Director General
European Molecular Biology Laboratory
Professor and Chair of Epigenetics and Cellular Memory
Collège de France

Title: Molecular mechanisms and 3D organisation during X inactivation

Abstract: In female mammals, one of the two X chromosomes becomes inactivated during early development in order to achieve X-chromosome dosage compensation between the sexes. X-chromosome inactivation (XCI) is usually initiated at random in eutherian mammals and the choice of inactive X is then stably propagated in somatic tissues, leading to clonal populations of cells expressing either the maternal or the paternal X. Thus females are cellular mosaics for X-linked allelic gene expression and this can lead to phenotypic variation both within and between individuals. There is also an increasing realization that the inactive X chromosome contributes to male-female differences in physiology and disease. Indeed, a significant proportion of X-linked genes can escape XCI and the increased dosage of proteins encoded by these genes can lead to genome-wide differences, influencing a wide variety of processes including cell differentiation and metabolism. My lab is interested in understanding how X-chromosome inactivation (XCI) is established and maintained, and how some genes escape XCI mainly using mouse as a model. Establishment of XCI involves the non-coding Xist RNA that coats the chromosome it is expressed from and triggers gene silencing as well as chromatin changes and 3D re-organisation of the X. Our recent work has focused on the role of Xist RNA’s partners in mediating these changes, in particular the SPEN protein, which acts as a platform for multiple factors acting on transcription, chromatin and RNA metabolism. Although most X-linked genes are sensitive to Xist RNA and SPEN in mouse XCI, different genes along the X show very different timing and extent of gene silencing and we are exploring the genetic and epigenetic basis for this differential gene silencing. This should provide important insights into precise mechanisms of transcriptional repression. We are also interested in understanding how some genes along the X chromosome display varying extents of escape from XCI and how this may be linked to sex-biased disorders. Our recent work exploring the process of XCI and the implications of variable expression from the inactive X chromosome will be presented.

Biography: Professor Edith Heard obtained her PhD from the Imperial Cancer Research Fund (later Cancer Research UK), London. Thereafter, she spent nine years at the Institut Pasteur in Paris, before undertaking a one-year sabbatical at Cold Spring Harbor in the USA. In 2001, she set up her group at the Institut Curie and in 2010 she became Director of the Institute’s Genetics and Developmental Biology Unit. Edith was appointed as a Professor of the Collège de France in 2012, holding the Chair of Epigenetics and Cellular Memory. Since January 2019, Edith has been Director General of EMBL.

Edith’s laboratory focuses on understanding how chromatin and chromosome organisation participate in gene regulation in development and disease. Her group was among the first to show that the epigenetic process of X-chromosome inactivation (XCI), whereby one of a female’s two X chromosomes is silenced during development, is remarkably dynamic. Her lab has worked out many of the molecular mechanisms underlying X-chromosome inactivation and she uses this model to explore fundamental principles of gene regulation, chromatin and epigenetic processes in general. Edith’s group was one of the first to uncover the epigenetic dynamics of XCI during mammalian development and they have provided insights into the regulation and molecular action of the Xist non-coding RNA that triggers XCI.  

Edith and her laboratory have been recognised by many prizes, most recently the L’Oréal-UNESCO For Women in Science International Award, Royal Society Croonian Medal (UK) and CNRS Gold Medal (France). She is a Fellow of the Royal Society, an EMBO Member, and a Foreign Associate member of the National Academy of Sciences (US), an International Member of the National Academy of Medicine (US), a Member of the German National Academy of Sciences Leopoldina, a Corresponding Member of the Royal Academy in Denmark, an Elected Member of Académie des Sciences, Institut de France, and she has an Honorary Degree Doctor of Science Honoris causa at the University of Cambridge, an Honorary Professor Degree at the University of Heidelberg and an Honorary Doctor Degree at the University of Uppsala.

Edith has participated in numerous scientific boards and is currently a member of the Scientific Advisory Board of the Crick Institute (London, UK), Institute Curie (Paris, France) and the WHO Science Council.

John Blenis, PhD
Anna-Maria and Stephen Kellen Professor in Cancer Research
Associate Director of Basic Science and Shared Resources
Sandra and Edward Meyer Cancer Center
Professor of Pharmacology
Director of Pharmacology PhD Program
Weill Cornell Medicine

Title: TOR, the gateway from growth factors and nutrients to RNA processing and metabolism

Abstract: mTOR complex 1 is regulated by growth factors, amino acids, a variety of nutrients, oxygen status and stress.  Once activated, this protein kinase controls many effectors, including downstream protein kinases such as S6K1, GSK3 and SRPK2. These in turn, regulate transcription, RNA processing, post-translational modifications and the function of downstream targets. These pathways are coordinated to provide proper regulation of cell growth and proliferation. Improper regulation by nutrient overload can yield mTORC1-driven metabolic diseases such as obesity, diabetes, heart disease and neurodegenerative diseases. When this system is highjacked by oncogenes and tumor suppressors, mTORC1 promotes tumorigenesis. I will describe one system linking mTORC1 to lipid metabolism, that involves S6K1-dependent posttranslational modifications of SRPK2, its spatial redistribution, the coordinated assembly of SREBP1, transcriptional co-regulator FAM120A, and splicing factors into a complex that couples transcription, proper splicing and lipid metabolism.

Biography: Dr. John Blenis is the Anna Maria and Stephen Kellen Professor of Cancer Research and Professor of Pharmacology in the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. He is also the Associate Director of Basic Science and Shared Resources at The Sandra and Edward Meyer Cancer Center. He served as the director of the pharmacology Ph.D. program for 3 x 3-year terms and is currently focusing on an effort to enhance Weill Cornell Medicine-NYC and Cornell-Ithaca cross campus programs, initially focused on cell metabolism. Dr. Blenis earned his B.A. from University of California, Berkeley, where he began studying the role of the Src tyrosine kinase in regulating the extracellular matrix. With his advisor, he moved to Michigan State University where he earned his Ph.D. in 1983.  His postdoctoral research in the Department of Cellular and Developmental Biology at Harvard University with Professor Raymond Erikson, was immediately followed by an appointment as Assistant Professor at Northwestern University Medical School in 1987. In 1989, he was recruited to Harvard Medical School as an Assistant Professor, was promoted to Associated Professor in 1993, and quickly promoted to Professor in 1996. In 2014, he was recruited to Weill Cornell Medicine in New York City to help establish the foundation needed to build the newly formed Meyer Cancer Center. 

Chris Benner, PhD
Associate Professor
Department of Medicine
UC San Diego

Title: Leveraging transcription initiation in the immune system to decode cis-regulatory grammar

Abstract: Patterns of transcriptional activity are encoded in our genome through regulatory elements such as promoters or enhancers that contain similar assortments of sequence-specific transcription factor (TF) binding sites. Knowledge of how these sequence motifs encode multiple, often overlapping, gene expression programs is central to understanding gene regulation and how mutations in non-coding DNA manifest in disease. By studying gene regulation from the perspective of individual transcription start sites (TSSs), we show that the effect of TF binding on transcription initiation is position dependent. Leveraging initiation profiling methods developed in the lab (csRNA-seq and TSS-MPRA), we demonstrate that several TFs can activate or repress transcription initiation depending on their precise position relative to the TSS. As such, TFs and their spacing collectively guide the site and frequency of transcription initiation within regulatory elements, directing their response to different stimuli or pathological conditions. More broadly, these findings reveal how similar assortments of TF binding sites can generate distinct gene regulatory outcomes depending on their spatial configuration and how DNA sequence polymorphisms may contribute to transcription variation and disease and underscore a critical role for TSS data in decoding the regulatory information of our genome.

Biography:

Dr. Benner is a genomics/bioinformatics scientist studying how gene regulatory programs are encoded by the genome. He conducted his graduate studies at the University of California, San Diego (UCSD) as part of the Bioinformatics Graduate Program in the laboratory of Dr. Christopher Glass, where he developed analysis tools to study immune cell differentiation and activation using next-generation sequencing and bioinformatics methods (NGS). After a brief post-doc, he joined the Salk Institute as the Director of the Integrative Genomics Core, assisting dozens of laboratories with the analysis and interpretation of genomics assays across a wide range of experimental systems, disease models, and organisms. He was subsequently recruited to join the faculty at UCSD, where his current laboratory explores how genomic sequence, epigenetics, and 3D chromatin structure interact with one another to regulate transcription.

Dr. Benner’s most notable career accomplishment is the development of HOMER, a software suite used to analyze data from numerous NGS assays and identify DNA motifs in regulatory sequences (>10k citations). His current work focuses on developing assays and analysis tools that leverage nascent transcription initiation to unravel the cis-regulatory grammar governing how transcription factors are organized in regulatory elements. The laboratory uses these unique approaches to model how transcriptional networks respond to inflammatory stimulation or other pathological conditions and monitor the impact that non-coding genetic variation plays in perturbing transcriptional responses. Dr. Benner also collaborates with multiple groups to study viral host-pathogen interactions, cellular development, substance abuse, and other diseases and experimental systems while continuing to develop genomics software, exemplified by HOMER and the pathway enrichment tool METASCAPE, to improve the interpretation of genomics data.

Diana Hargreaves, PhD
Associate Professor
Richard Heyman and Anne Daigle Endowed Developmental Chair
Molecular and Cell Biology Laboratory
Salk Institute

Title: SWI-SNF Complexes in Development and Disease

Abstract: Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.

Biography: Diana Hargreaves joined the Salk Institute as an Assistant Professor in the Molecular and Cell Biology Laboratory in 2015. She holds the Richard Heyman and Anne Daigle Endowed Developmental Chair. Her lab researches the role of the SWI/SNF chromatin remodeling complexes in inflammation and anti-tumor immune responses. Additionally, she is aiming to uncover how mutations in the SWI/SNF complex shape the tumor microenvironment and influence the response to immunotherapy. She is the recipient of the American Cancer Society Research Scholar Award, the Pew-Stewart Scholar for Cancer Research Award, as well as the V Foundation Scholar Award.

Arthur Lander, MD, PhD
Donald Bren Professor
Department of Developmental and Cell Biology
Director of the Center for Complex Biological Systems
UC Irvine

Title: Non-genetic transitions as rate-limiting steps in cancer

Abstract: Abundant evidence exists that cancer arises and progresses through discrete, rare events that act as slow, rate-limiting steps.  Somatic mutations account for many of these steps, and interest in cancer-associated mutations has fueled much of the cancer research of the last four decades.  Yet a growing body of evidence makes it increasingly unlikely that all rate-limiting steps in cancer correspond to mutations.  Animal models, in which engineered mutations are created in thousands to millions of cells of which only a small fraction develop into tumors, have been particularly important in suggesting the existence of non-genetic transitions in cancer initiation, and I will discuss recent data that support this view.  Yet the fact that such events must be rare (lest they not be rate-limiting) makes them difficult to envision: What other important things, besides mutation, happen to cells with such low probability?  A popular model invokes spontaneous stable change to the epigenome, also known as “epimutation”, that durably alters gene expression. Yet opportunities for spontaneous, rare state switching easily emerge out of other biological processes, from gene regulatory networks to networks of cell-cell interaction. I will describe surprising mechanisms by which non-cell autonomous (i.e., collective) transitions to uncontrolled cell proliferation may be expected to emerge directly out of circuits of cell communication that normally function to control tissue growth and size. The inherent reversibility of collective transitions makes them attractive targets for cancer therapy and, as I will argue, offers a means by which to understand puzzles such as cancer dormancy. 

Biography: Dr. Lander enjoys doing Systems Biology, fusing experimental biology with mathematics, physics, engineering and computer science, in the search for fundamental design principles that explain the complexity of life.  He received his B.S. degree in Molecular Biophysics and Biochemistry from Yale, followed by an M.D. degree and a Ph.D. in neuroscience from the University of California, San Francisco. After postdoctoral research in neurobiology at Columbia University, he joined the faculty of the Massachusetts Institute of Technology, in the Departments of Brain & Cognitive Sciences and Biology. He later moved to UC Irvine, where he founded and currently directs the Center for Complex Biological Systems, which fosters interdisciplinary research, training, and outreach at the interface between biology and the physical, computational, and engineering sciences. He also co-directs UCI’s Cancer Systems Biology Center, is an Associate Director of the NSF-Simons Center for Multi-scale Cell Fate Research, and leads the Systems Biology core of UCI’s Skin Biology Research Center.

His research has focused on how cells accurately know their locations in space; how tissues and organs stop growing at precisely-determined sizes; and how selection for control of these processes opens the door to combinatorial fragility, wherein combinations of small changes (e.g. in gene expression) can lead to catastrophic failures (e.g. birth defects).  Dr. Lander’s honors include a David and Lucille Packard Fellowship for Science and Engineering; an NIH-Javits Neuroscience Investigator Award; and a RARE Champion of Hope in Science Award, as well as election to membership in the American Society for Clinical Investigation and fellowship in the American Association for the Advance of Science. He is a member of the Clinical Advisory Board and Board of Directors of the Cornelia de Lange Syndrome Foundation, and advocates globally for systems biology through visiting appointments at the University of Tsukuba, in Japan, and National Taiwan University.

Ludmil Alexandrov, PhD
Professor
Department of Cellular and Molecular Medicine
Department of Bioengineering
UC San Diego

Title: Geographic and age-related variations in mutational processes in colorectal cancer

Abstract: Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

Biography: Ludmil Alexandrov is a Professor at the University of California, San Diego, with joint appointments in the Departments of Bioengineering and Cellular and Molecular Medicine. His research is dedicated to harnessing the wealth of information in large-scale omics datasets to better understand the mutagenic and non-mutagenic processes driving cancer initiation and progression. His goal is to use this knowledge to uncover new cancer prevention strategies and develop innovative, targeted treatment approaches. He is also passionate about advancing AI to address inequalities in cancer prevention, diagnosis, and care. Over the past decade, his work has centered on developing the concept of mutational signatures, demonstrating their value in understanding human cancer, and identifying these signatures across a wide range of cancer types. He believes that by integrating next-generation machine learning techniques with novel experimental methods, his lab can achieve a predictive understanding of the fundamental molecular processes driving cancer. This will enable researchers to improve cancer treatment and prevention.