Genomes and Genes
Role of the pRB family in Quiescence and Differentiation
Principal Investigator: BRIAN DYNLACHT
Affiliation: New York University
Abstract: [unreadable] DESCRIPTION (provided by applicant): The retinoblastoma tumor suppressor protein (pRB) and the related proteins p107 and p130 (collectively termed "pocket" proteins) play an established role in suppressing cell growth through inhibition of the E2F transcription factor. A role for the pRB family in cell cycle exit and muscle differentiation has also been documented. While cellular quiescence and p16INK4a-induced growth arrest appear to require combinations of "pocket" proteins, specific pRB family members have been implicated in terminal differentiation of muscle cells. However, very few direct, physiological targets have been linked to cellular quiescence, and fewer direct targets associated with differentiation have been identified. Furthermore, pRB binding to promoters has not been widely observed in cultured fibroblasts during the cell cycle, raising interesting and important questions regarding the role of pRB in tumor suppression and suggesting that pRB's tumor suppressive function may involve a much more extensive role in promoting differentiation than previously imagined. One goal of this proposal is to identify and characterize (1) direct, physiological targets of the pRB family involved in achieving cellular quiescence and p161NK4a -mediated growth arrest and (2) those gene targets that cooperate to confer irreversible cell cycle exit and terminal differentiation of muscle. It will also attempt to distinguish between those controls involved in cell cycle withdrawal and phenotypic differentiation. This will be accomplished through large-scale analyses of "pocket" protein binding to the genome of living cells (factor location analysis) during the process of cell cycle exit and differentiation, through simultaneous analysis of gene expression profiles, and through biochemical dissection of target promoters. By examining three cell cycle exit pathways that appear to require certain pRB family members but not others, this work will have a fundamental impact on our understanding of the existence of gene regulatory networks effecting cell cycle exit in response to distinct biological cues. pRB plays a well-documented role in growth control, and inactivation of this tumor suppressor has been associated with a large proportion of human cancers. This Proposal is therefore highly relevant to our understanding of tumor suppressive mechanisms and cancer.
Funding Period: 2003-02-01 - 2007-09-19
more information: NIH RePORT
- A role for H3K4 monomethylation in gene repression and partitioning of chromatin readersJemmie Cheng
Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY 10016, USA
Mol Cell 53:979-92. 2014..Our findings point to a unique role for H3K4 monomethylation in establishing boundaries that restrict the recruitment of chromatin-modifying enzymes to defined regions within promoters. ..
- The role of MyoD1 and histone modifications in the activation of muscle enhancersRoy Blum
Department of Pathology and Cancer Institute Smilow Research Center New York University School of Medicine New York, NY USA
Epigenetics 8:778-84. 2013..Thus, MyoD1 and enhancer-associated transcription factors function coordinately to assemble and regulate enhancers, thereby augmenting expression of muscle-related genes. ..
- Genome-wide identification of enhancers in skeletal muscle: the role of MyoD1Roy Blum
Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
Genes Dev 26:2763-79. 2012..Our studies identified a role for MyoD1 in condition-specific enhancer assembly through recruitment of transcription factors and histone-modifying enzymes that shape muscle differentiation...
- Picking ChIP-seq peak detectors for analyzing chromatin modification experimentsMariann Micsinai
Yale University School of Medicine, Department of Pathology, New Haven, CT 06520, USA
Nucleic Acids Res 40:e70. 2012..This study also provides a reproducible and generalizable methodology for unbiased comparative analysis of high-throughput sequencing tools that can facilitate future algorithmic development...
- Dynamic loss of H2B ubiquitylation without corresponding changes in H3K4 trimethylation during myogenic differentiationVasupradha Vethantham
Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, New York, USA
Mol Cell Biol 32:1044-55. 2012..Thus, muscle cells represent a novel setting in which to explore mechanisms that regulate histone cross talk...
- Genome-wide remodeling of the epigenetic landscape during myogenic differentiationPatrik Asp
Department of Pathology and Cancer Institute, New York University School of Medicine, 522 First Avenue, Smilow Research Building 1104, New York, NY 10016, USA
Proc Natl Acad Sci U S A 108:E149-58. 2011....
- The mammalian Sin3 proteins are required for muscle development and sarcomere specificationChris van Oevelen
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA
Mol Cell Biol 30:5686-97. 2010..Thus, our analyses describe a novel transcriptional role for Sin3A and Sin3B proteins associated with maintenance of differentiated muscle cells...
- Traf7, a MyoD1 transcriptional target, regulates nuclear factor-κB activity during myogenesisMary Tsikitis
Department of Pathology, New York University School of Medicine, New York 10016, USA
EMBO Rep 11:969-76. 2010..Our results suggest a new mechanism by which MyoD1 function is coupled to NF-κB activity through Traf7, regulating the balance between cell cycle progression and differentiation during myogenesis...
- Retinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exitAlexandre Blais
Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa K1H 8M5, Canada
J Cell Biol 179:1399-412. 2007..H3K27 trimethylation silences other genes, including Cyclin D1, in a pRb-independent but polycomb-dependent manner. Thus, our data distinguish two distinct chromatin-based regulatory mechanisms that lead to terminal differentiation...
- XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networksDiego Acosta-Alvear
New York University School of Medicine, New York, NY 10016, USA
Mol Cell 27:53-66. 2007..Our results provide a detailed picture of the regulatory roadmap governed by XBP1 in distinct cell types as well as insight into unexplored functions of XBP1...
- Functional genomics via multiscale analysis: application to gene expression and ChIP-on-chip dataGilad Lerman
Department of Mathematics, University of Minnesota, 127 Vincent Hall, 206 Church St S E, Minneapolis, MN 55455, USA
Bioinformatics 23:314-20. 2007..We show how to accommodate the unique characteristics of ChIP-on-chip data, where the set of 'enriched targets' is large, asymmetric and whose proportion to the whole data varies locally...
- Constructing transcriptional regulatory networksAlexandre Blais
Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA
Genes Dev 19:1499-511. 2005..These approaches should allow us to elucidate complete transcriptional regulatory codes for yeast as well as mammalian cells...
- New insights into cyclins, CDKs, and cell cycle controlIRMA SANCHEZ
Department of Pathology, MSB 504, New York University School of Medicine, NYU Cancer Institute, 550 First Avenue, New York, NY 10016, USA
Semin Cell Dev Biol 16:311-21. 2005..Many recent surprises have come to light recently as a result of genetic manipulation of cells and mice, and these findings suggest that our understanding of the intricacies of the cell cycle is still rudimentary at best...