Role of the pRB family in Quiescence and Differentiation

Summary

Principal Investigator: BRIAN DYNLACHT
Affiliation: New York University
Country: USA
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

Top Publications

  1. pmc A role for H3K4 monomethylation in gene repression and partitioning of chromatin readers
    Jemmie 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
  2. pmc The role of MyoD1 and histone modifications in the activation of muscle enhancers
    Roy 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
  3. pmc Genome-wide identification of enhancers in skeletal muscle: the role of MyoD1
    Roy Blum
    Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
    Genes Dev 26:2763-79. 2012
  4. pmc Picking ChIP-seq peak detectors for analyzing chromatin modification experiments
    Mariann Micsinai
    Yale University School of Medicine, Department of Pathology, New Haven, CT 06520, USA
    Nucleic Acids Res 40:e70. 2012
  5. pmc Dynamic loss of H2B ubiquitylation without corresponding changes in H3K4 trimethylation during myogenic differentiation
    Vasupradha 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
  6. pmc Genome-wide remodeling of the epigenetic landscape during myogenic differentiation
    Patrik 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
  7. pmc The mammalian Sin3 proteins are required for muscle development and sarcomere specification
    Chris van Oevelen
    Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA
    Mol Cell Biol 30:5686-97. 2010
  8. pmc Traf7, a MyoD1 transcriptional target, regulates nuclear factor-κB activity during myogenesis
    Mary Tsikitis
    Department of Pathology, New York University School of Medicine, New York 10016, USA
    EMBO Rep 11:969-76. 2010
  9. pmc Retinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit
    Alexandre 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
  10. ncbi XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks
    Diego Acosta-Alvear
    New York University School of Medicine, New York, NY 10016, USA
    Mol Cell 27:53-66. 2007

Scientific Experts

  • BRIAN DYNLACHT
  • Yuval Kluger
  • IRMA SANCHEZ
  • Gilad Lerman
  • Roy Blum
  • Alexandre Blais
  • Christopher Bowman
  • Patrik Asp
  • Jemmie Cheng
  • Vasupradha Vethantham
  • Mariann Micsinai
  • Diego Acosta-Alvear
  • Fabio Parisi
  • Mary Tsikitis
  • Chris van Oevelen
  • Steven Shen
  • Deqing Hu
  • Ali Shilatifard
  • David G Skalnik
  • Jeong Heon Lee
  • Michael Rudnicki
  • Yan Yang
  • Francesco Strino
  • Jessica Pellegrino
  • Gregory David
  • Eric I Campos
  • William S Lane
  • Alphonse Chu
  • Christen J Lennon
  • Yiming Zhou
  • Chris J C van Oevelen
  • Carolina Arias
  • Nathan H Lents
  • Raphael Margueron

Detail Information

Publications13

  1. pmc A role for H3K4 monomethylation in gene repression and partitioning of chromatin readers
    Jemmie 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. ..
  2. pmc The role of MyoD1 and histone modifications in the activation of muscle enhancers
    Roy 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. ..
  3. pmc Genome-wide identification of enhancers in skeletal muscle: the role of MyoD1
    Roy 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...
  4. pmc Picking ChIP-seq peak detectors for analyzing chromatin modification experiments
    Mariann 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...
  5. pmc Dynamic loss of H2B ubiquitylation without corresponding changes in H3K4 trimethylation during myogenic differentiation
    Vasupradha 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...
  6. pmc Genome-wide remodeling of the epigenetic landscape during myogenic differentiation
    Patrik 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
    ....
  7. pmc The mammalian Sin3 proteins are required for muscle development and sarcomere specification
    Chris 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...
  8. pmc Traf7, a MyoD1 transcriptional target, regulates nuclear factor-κB activity during myogenesis
    Mary 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...
  9. pmc Retinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit
    Alexandre 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...
  10. ncbi XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks
    Diego 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...
  11. ncbi Functional genomics via multiscale analysis: application to gene expression and ChIP-on-chip data
    Gilad 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...
  12. ncbi Constructing transcriptional regulatory networks
    Alexandre 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...
  13. ncbi New insights into cyclins, CDKs, and cell cycle control
    IRMA 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...