Overview

Stem cells are essential for metazoan development and for the maintenance of tissue homeostasis in the adult organism. Embryonic stem (ES) cells can be derived from the mammalian pre-implantation embryo and have enormous therapeutic potential because they can propagated in vitro while maintaining the capacity to give rise to all cell types in the body. A major challenge in biology is to understand how these undifferentiated cells execute the diverse gene expression programs that lead to cellular specification. Chromatin organization is a fundamental mechanism used by all eukaryotes to compartmentalize the genome into functional domains in order to interpret the vast amount of genetic information encoded within the genome. The overall goal of the lab is to understand how chromatin structure influences gene expression programs and ultimately cell fate and how failure to establish proper chromatin states can contribute to disease. To address these questions, we use a combination of genomic, genetic, biochemical and cell biological tools to precisely characterize the factors involved in regulating chromatin structure, to determine how these factors are recruited to genomic sites, and to investigate how these different regulatory pathways cooperate to organize the genome. We are particularly interested in how specific chromosomal domains are assembled and propagated in ES cells, adult stem cells, and somatic cells. Discovering how gene expression programs are regulated is required to improve our understanding of development and disease, and for realizing the therapeutic potential of stem cells.

Research Summary

Chromatin regulation during development: Chromatin structure and composition play an important role in regulating gene expression and cellular identity. How active and silent chromosomal domains are assembled and propagated during development is not well understood. ES cell chromatin is generally characterized by an open, nuclease-sensitive conformation and by the dynamic association of histones and associated proteins. Chromatin reorganization and heterochromatin formation is essential for the establishment of new heritable gene expression states that accompany lineage specification. The mechanisms that control these processes, however, are poorly understood.

Heterochromatin is a major component of all metazoan genomes and regulates many processes including chromosome segregation, nuclear organization, and transcriptional gene silencing. Heterochromatin comprises large “constitutive” domains, such as pericentric regions, that are thought to be critical for chromosome segregation and genome integrity. Heterochromatin can also be assembled as more discrete domains in the promoter regions of autosomal genes during gene silencing or can encompass an entire chromosome as in the process of X-inactivation (facultative heterochromatin). Heterochromatin has been particularly refractory to study in mammalian systems because of the complexity and intricate regulation of this structure. It is our goal to functionally characterize the factors involved in regulating heterochromatin formation during development and differentiation and to understand how this structure influences genomic integrity, gene regulation, and ultimately cell fate.

The role of Polycomb group proteins in transcriptional gene silencing: Polycomb group (PcG) proteins are essential for metazoan development and function in heterochromatic gene silencing by post-translational modification of histone proteins. PcG group proteins have been shown to play key roles in stem cell maintenance in a variety of organisms. Our recent work has shown that PcG proteins control a large cohort of genes with known roles in development in both mouse and human ES cells, whose expression would otherwise promote differentiation and loss of pluripotency. How these epigenetic regulators are targeted to specific genomic sites in ES and how PcG proteins influence chromatin structure to allow for proper control of developmental gene expression programs during differentiation is an important and unresolved question. Evidence in a variety of eukaryotes suggests that the RNAi machinery as well as large noncoding RNAs are necessary for pericentric heterochromatin formation and may play a role in the recruitment of PcG proteins to their target genes. We are particularly interested in investigating a role for RNA molecules in mediating silencing through direct (cis) recruitment of PcG proteins as well as by more indirect long-range (trans) interactions.

The role of histone variants in chromatin dynamics during development: Histone variants are evolutionarily conserved non-allelic variants of the major histone proteins that can have significant differences in their primary sequence and on the biophysical properties of nucleosomes. Unlike the cannonical histones, variants are expressed throughout the cell cycle, deposited into chromatin in a replication-independent manner, and are thought to have evolved specialized functions. Histone variants can localize to discrete regions of the genome and play important roles in genome integrity, gene regulation, X-inactivation, and DNA repair. The evolutionarily conserved H2A variant, H2AZ, is essential for metazoan development and has been implicated in heterochromatin formation and gene regulation from fungi to plants to metazoans. Notably, loss of H2AZ results in early embryonic lethality prior to implantation in mice, however the function of H2AZ during mammalian development remains unclear. Our goal is to elucidate the mechanisms by which histone variants such as H2AZ contribute to development through establishment and maintenance of specialized chromatin domains.

Selected Publications

Guenther MG*, Levine SS*, Boyer LA, Jaenisch R, Young RA (2007) A Chromatin Landmark and Transcription Initiation at Most Promoters in Human Cells. Cell, 130 77-88. *These authors contributed equally. Featured article in Cell.

Boyer LA, Mathur D, Jaenisch R (2006) Molecular control of pluripotency. Curr Opin Genet Dev, 16(5) 455-462.

Boyer LA*, Plath K*, Zeitlinger J, Brambrink T, Medeiros L, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R (2006) Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature, 441 349-353. Epub 2006 April 19. *These authors contributed equally. Accompanied by Preview in Cell 125, 233-236; Science 312, 349.

Lee TI*, Jenner RG*, Boyer LA*, Guenther MG*, Levine SS*, Chevalier B, Murray HL, Johnstone SE, Kumar RM, Zucker JP, Yuan B, Bell GW, Herbolsheimer E, Hannett NM, Cole MF, Sun K, Guenther MG, Odom DT, Volkert TL, Bartel DP, Gifford DK, Melton DA, Jaenisch R, Young RA (2006) Control of developmental regulators in human embryonic stem cells. Cell, 125 310-313. *These authors contributed equally. Featured Article and Accompanied by Preview in Cell 125, 233-236; Science 312, 349.

Cao Y, Kumar RM, Penn BH, Berkes CA, Kooperberg CL, Boyer LA, Young RA, Tapscott SJ. (2006) Global and promoter-specific analyses reveal distinct roles for Myod and Myog at a common set of regulatory regions. EMBO J, 25 502-511.

Boyer LA*, Lee TI*, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (2005) Core transcriptional regulatory network in human embryonic stem cells, Cell 122 947-956. *These authors contributed equally. Featured Article and Accompanied by Preview in Cell 122, 828-830.

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