Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

ABSTRACT

Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G₁ phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention.

KEYWORDS:

• bivalency
• cancer
• epigenetic control
• nuclear structure
• oncofetal gene expression

ACKNOWLEDGMENTS

The work in our laboratories that is discussed in this review was supported by a Pfizer Investigator-Initiated Research Award (WS2049100), by an NIH Program Project grant (P01 CA 082834), by an NCI Consortium grant (U01 CA 196383), and by the Charlotte Perelman Fund for Cancer Research.

Additional information

Notes on contributors

Sayyed K. Zaidi

Sayyed K. Zaidi received his Ph.D. from University of the Punjab, Pakistan, and postdoctoral training from University of Massachusetts Medical School, Worcester, MA, where he was a research assistant professor from 2008 to 2012. He is currently an associate professor in the Department of Biochemistry at the University of Vermont and an associate director for regional collaborations in the University of Vermont Cancer Center. Dr. Zaidi's research interests include epigenetic control of gene expression, mechanisms of leukemogenesis, mitotic gene bookmarking, and higher-order nuclear organization.

Seth E. Frietze

Seth E. Frietze received his Ph.D. from Harvard University. He served both as a postdoctoral fellow at the University of Southern California and as a visiting faculty fellow at Los Alamos National Laboratories. Dr. Frietze is currently an assistant professor in the Department of Medical Laboratory Sciences at the University of Vermont. His research interests over the last 10 years have focused on understanding the role of altered epigenetic programs during tumorigenesis.

Jonathan A. Gordon

Jonathan A. Gordon carried out his doctoral research at the University of Western Ontario, London, Ontario, Canada. He was previously a research assistant professor, Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA. Currently, Dr. Gordon is an assistant professor in the Department of Biochemistry at University of Vermont. Dr. Gordon's research has focused on understanding the mechanisms of bone marrow-derived mesenchymal stem cell (MSC) commitment to osteogenic lineages and their involvement in malignant disease processes, such as metastatic niches and tumor microenvironments. The differentiation of MSCs as a normal process (such as bone development) or as an aberrant process due to association with neoplastic tissues is regulated by transcriptional regulators, early chromatin remodeling events, and epigenetic modifiers. These epigenetic processes have obvious implications for controlling MSC commitment, potentially leading to novel therapies to increase bone mass under chronic disease conditions or to interfere with unwanted differentiation in cancer-associated environments.

Jessica L. Heath

Jessica L. Heath received her bachelor of science degree in biology from Cornell University and her doctor of medicine degree from the State University of New York at Stony Brook. She then completed her pediatric residency training at Albany Medical Center, followed by fellowships in pediatric hematology-oncology and intensive research training in pediatric oncology at Duke University. She was a medical instructor in the Division of Pediatric Hematology-Oncology at Duke University prior to accepting her current position as assistant professor of pediatrics and biochemistry at the University of Vermont in 2015. Dr. Heath has been studying the molecular underpinnings of aggressive pediatric leukemias, with a focus on epigenetic mechanisms of disease, for the past 7 years. Her focus is on translational cancer biology, with the goal of developing novel targeted therapeutics for high-risk pediatric leukemias.

Terri Messier

Terri Messier is a research analyst in the Department of Biochemistry at the University of Vermont and in the University of Vermont Cancer Center. She received her undergraduate education at the University of Vermont in the Department of Laboratory Sciences. Her biomedical research experience consists of over 30 years of work in both the academic and biotechnology sectors, including projects in several laboratories at the University of Vermont in Burlington, and as a group leader at Acadia Pharmaceuticals in San Diego, CA. Her research interests include development of improved detection and treatment modalities in cancer by studying both genetic and epigenetic changes that result in transcriptional reprograming of cancer cells.

Deli Hong

Deli Hong received a master of science degree from the Department of Chemistry and Biochemistry, Worcester Polytechnic Institute. Between 2009 and 2010, he worked as a Research Associate in Kendall Knight's laboratory in the Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School. Currently, Mr. Hong is a Ph.D. student in the Graduate Program of Cell Biology, University of Massachusetts Medical School. His work is focused on understanding the mechanisms of breast cancer progression. Epithelium-to-mesenchyme transition (EMT) has been implicated as an essential process in breast cancer metastasis and chemoresistance. Understanding the epigenetic silencing of E-cadherin, a key mechanism activating EMT, can help the development of promising targets for the prevention of metastasis.

Joseph R. Boyd

Joseph R. Boyd received his master's degree in bioinformatics and computational biology from Worcester Polytechnic Institute. He is currently the bioinformatician for the Stein-Lian research group at the University of Vermont. He has been processing and analyzing transcriptome sequencing (RNA-seq), ChIP-seq, and comparative high-throughput chromosome conformation capture (Hi-C) datasets for three years. His primary interest is in constructing application-specific interactive visualizations to enable biologists to analyze their omics-scale data. Joseph enjoys the challenges posed by the task of distilling meaningful information from the deluge of data available with the advent of next-generation sequencing.

Mingu Kang

Mingu Kang received his bachelor's degree in biology at the University of Oregon. After graduation, he worked for a year as a laboratory technician at the Korea Research Institute of Bioscience and Biotechnology (KRIBB). He received a master's degree in biochemistry and molecular medicine at George Washington University. Currently, he is a Ph.D. student in the Cellular, Molecular, and Biomedical Sciences Program at the University of Vermont. His primary focus is in epigenetic cell reprogramming related to the functions of various histone modifications during cancer progression. Specifically, a unique epigenetic feature known as bivalency provides flexibility in gene expression. He has been investigating the resulting control of cellular plasticity as a key regulatory mechanism in the reprograming of cancer cells in the Stein-Lian laboratory for a year.

Anthony N. Imbalzano

Anthony N. Imbalzano is professor of biochemistry and molecular pharmacology and associate dean, Office for Postdoctoral Scholars, at the University of Massachusetts Medical School. He and his fellow laboratory staff members have had a long-term interest in the roles of SWI/SNF chromatin remodeling enzymes in controlling gene expression, chromatin structure, and high-order genome organization in differentiation and in cancer. Tony received his Ph.D. in microbiology and molecular genetics with Neal DeLuca at Harvard University and did postdoctoral studies with Bob Kingston at Massachusetts General Hospital.

Jane B. Lian

Jane B. Lian is a professor in the biochemistry Department at the University of Vermont and codirector of a Translational Research Program of the University of Vermont Cancer Center. Dr. Lian received her Ph.D. from Boston University Medical School and held faculty positions at the Children's Hospital, Harvard Medical School, and at University of Massachusetts Medical School. Her research programs for over 3 decades have investigated the genetic and epigenetic mechanisms regulating osteoblast growth and differentiation. Dr. Lian contributed to discovery of the bone-specific c protein osteocalcin and the Runx2 transcription factor, essential for bone formation. Her investigations established Runx2 as a mediator of signaling pathways activated during osteogenesis and in tumor cells causing metastatic bone disease. Dr. Lian's studies have received recognition in the form of several prestigious awards, including awards from the American Academy of Orthopedic Surgeons and from the American Society for Bone and Mineral Res She has published over 400 peer-reviewed articles and numerous reviews.

Janet L. Stein

Janet L. Stein received her Ph.D. in chemistry from Princeton University and pursued her postdoctoral training in the Department of Biochemistry and Molecular Biology at the University of Florida. She has held faculty positions in the Department of Immunology and Medical Microbiology at the University of Florida and the Department of Cell Biology at University of Massachusetts Medical School. She is currently a Professor in the Department of Biochemistry at the University of Vermont and a program leader at the UVM Cancer Center. Her major research contributions to science include insights into alterations in nuclear organization and chromatin in cancer and histone gene regulation and its influence on cell cycle control, the abbreviated cell cycle that characterizes pluripotent stem cells, and mechanisms for transcription factor targeting and mitotic retention at gene loci.

Gary S. Stein

Gary S. Stein trained in biology and pathology and is dedicated to basic, translational, and clinical cancer investigation. He pioneered discovery of mechanisms controlling proliferation and differentiation, emphasizing compromised genetic and epigenetic regulation in cancer. His focus is on mechanisms and biomarkers, including noncoding RNAs associated with prostate, leukemia, and breast cancer prevention, and early detection, treatment, and survivorship. A priority is characterizing genetic and epigenetic regulation mediating cell cycle control and the abbreviated pluripotent cell cycle in human embryonic stem cells, induced pluripotent cells, and cancer stem cells. He is investigating breast and prostate tumor metastasis to bone, including microRNA-mediated control, and is defining mechanisms that govern the combinatorial organization and assembly of regulatory machinery in nuclear microenvironments and epigenetic control of cell fate and lineage commitment. Dr. Stein is currently the chairperson of the Department of Biochemistry at the University of Vermont and the Director of the University of Vermont Cancer Center.