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    Chromosome-Biased Binding and Function of C. elegans DRM Complex, and Its Role in Germline Sex-Silencing: A Dissertation

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    Authors
    Tabuchi, Tomoko M.
    Faculty Advisor
    Kirsten Hagstrom, Ph.D.
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Program in Molecular Medicine and Program in Cell Dynamics
    Document Type
    Doctoral Dissertation
    Publication Date
    2011-07-21
    Keywords
    DRM
    X-chromosomes
    Development
    C.elegans
    X-silencing
    Chromosome-biased binding
    Caenorhabditis elegans
    Caenorhabditis elegans Proteins
    Transcription Factors
    Trans-Activators
    Chromosomes
    Human
    X
    Gene Expression Regulation
    Amino Acids, Peptides, and Proteins
    Animal Experimentation and Research
    Cell and Developmental Biology
    Cells
    Genetic Phenomena
    Genetics and Genomics
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    Abstract
    DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in the cell cycle and cancer. Recent work has unveiled a new aspect of DRM function in regulating genes involved in development and differentiation. These studies, however, were performed with cultured cells and a genome-wide study involving intact organisms undergoing active proliferation and differentiation was lacking. Our goal was to extend the knowledge of the role of DRM in gene regulation through development and in multiple tissues. To accomplish this, we employed genomic approaches to determine genome-wide targets of DRM using the nematode Caenorhabditis elegans as a model system. In this dissertation, I focus on the DRM component LIN-54 since it was proposed to exhibit DNA-binding activity. First, we confirmed the DNA-binding activity of C.elegans LIN-54 in vivo, and showed it is essential to recruit the DRM complex to its target genes. Next, chromatin immunoprecipitation and gene expression profiling revealed that LIN-54 controls transcription of genes implicated in cell division, development and reproduction. This work identified an interesting contrast in DRM function in soma vs. germline: DRM promotes transcription of germline-specific genes in the germline, but prevents their ectopic expression in the soma. Furthermore, we discovered a novel characteristic of DRM, sex chromosome-biased binding and function. We demonstrated that C. elegans DRM preferentially binds autosomes, yet regulates X-chromosome silencing by counteracting the H3K36 histone methyltransferase MES-4. By using genomics, cytology, and genetics, we defined DRM as an important player in the regulation of germline X-chromosome gene expression, and addressed molecular mechanisms vii behind the antagonistic interactions between DRM and MES-4. I present a model to explain the interplay of DRM and MES-4, and propose a novel function of DRM and MES-4 in maintaining proper chromosome gene expression dosage. This work extends our knowledge of the conserved roles of DRM in development, and provides a new view of differing DRM functions in soma versus germline. Furthermore, we defined a novel chromosome-specific aspect of DRM-mediated regulation.
    DOI
    10.13028/7tnd-1156
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31877
    Notes

    This dissertation includes two supplemental spreadsheets for Chapter II. See Additional Files below.

    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/7tnd-1156
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