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RB-MEDIATED REGULATION OF TRANSCRIPTION AND EPIGENETIC MODIFICATIONS

SIDDIQUI, HASAN
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148053497

Abstract Details

2006, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.
The retinoblastoma tumor suppressor protein (RB) is the ‘master regulator’ of cellular proliferation and is targeted for inactivation in the majority of human tumors. RB inhibits proliferation by repressing the transcription of genes essential for cell cycle progression. Although RB interacts with numerous chromatin modifying (e.g., histone deacetylases or HDACs, histone methyltransferases or HMTases) and remodeling (e.g., SWI/SNF chromatin remodeling complex) enzymes, the functional significance of these interactions is not apparent. Here we investigated the role of chromatin modifying and remodeling enzymes in RB-mediated transcriptional repression and epigenetic modifications. We find that active RB mediates histone deacetylation on endogenous RB target gene promoters. We also demonstrate that this deacetylation is HDAC dependent, since the HDAC inhibitor trichostatin A (TSA) prevented histone deacetylation at each promoter. However, TSA treatment blocked RB repression of only a specific subset of genes, demonstrating that the requirement of HDACs for RB-mediated transcriptional repression is promoter specific. Furthermore, we find that cell cycle inhibitory action of RB is not intrinsically dependent on the ability to recruit HDAC activity. The HDAC-independent repression was not associated with DNA methylation or gene silencing since it was readily reversible. We show that this form of repression resulted in altered chromatin structure and was dependent on SWI/SNF chromatin remodeling activity. Importantly, we demonstrate that SWI/SNF is required for histone deacetylation of RB target promoters. Furthermore, we show that loss of RB disrupts a specific epigenetic modification and heterochromatin protein 1 (HP1) dynamics in the chromatin. These studies highlight the influence of RB on transcriptional repression and epigenetic modifications.
Erik Knudsen (Advisor)
190 p.
Cancer; Cell Cycle; Retinoblastoma tumor suppressor; Chromatin modifications; Transcription; SWI/SNF; HDAC

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Citations

  • SIDDIQUI, H. (2006). RB-MEDIATED REGULATION OF TRANSCRIPTION AND EPIGENETIC MODIFICATIONS [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148053497

    APA Style (7th edition)

  • SIDDIQUI, HASAN. RB-MEDIATED REGULATION OF TRANSCRIPTION AND EPIGENETIC MODIFICATIONS. 2006. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148053497.

    MLA Style (8th edition)

  • SIDDIQUI, HASAN. "RB-MEDIATED REGULATION OF TRANSCRIPTION AND EPIGENETIC MODIFICATIONS." Doctoral dissertation, University of Cincinnati, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1148053497

    Chicago Manual of Style (17th edition)

ucin1148053497
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© 2006, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.