mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival (original) (raw)

  1. Jan-Hermen Dannenberg1,4,
  2. Gregory David1,3,4,
  3. Sheng Zhong2,
  4. Jaco van der Torre1,
  5. Wing H. Wong2, and
  6. Ronald A. DePinho1,5
  7. 1Department of Medical Oncology, Dana Farber Cancer Institute; Departments of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA; 2Department of Statistics, Stanford University, Stanford, California 94305, USA

Abstract

mSin3A is a core component of a large multiprotein corepressor complex with associated histone deacetylase (HDAC) enzymatic activity. Physical interactions of mSin3A with many sequence-specific transcription factors has linked the mSin3A corepressor complex to the regulation of diverse signaling pathways and associated biological processes. To dissect the complex nature of mSin3A's actions, we monitored the impact of conditional mSin3A deletion on the developmental, cell biological, and transcriptional levels. mSin3A was shown to play an essential role in early embryonic development and in the proliferation and survival of primary, immortalized, and transformed cells. Genetic and biochemical analyses established a role for mSin3A/HDAC in p53 deacetylation and activation, although genetic deletion of p53 was not sufficient to attenuate the mSin3A null cell lethal phenotype. Consistent with mSin3A's broad biological activities beyond regulation of the p53 pathway, time-course gene expression profiling following mSin3A deletion revealed deregulation of genes involved in cell cycle regulation, DNA replication, DNA repair, apoptosis, chromatin modifications, and mitochondrial metabolism. Computational analysis of the mSin3A transcriptome using a knowledge-based database revealed several nodal points through which mSin3A influences gene expression, including the Myc-Mad, E2F, and p53 transcriptional networks. Further validation of these nodes derived from in silico promoter analysis showing enrichment for Myc-Mad, E2F, and p53 _cis_-regulatory elements in regulatory regions of up-regulated genes following mSin3A depletion. Significantly, in silico promoter analyses also revealed specific _cis_-regulatory elements binding the transcriptional activator Stat and the ISWI ATP-dependent nucleosome remodeling factor Falz, thereby expanding further the mSin3A network of regulatory factors. Together, these integrated genetic, biochemical, and computational studies demonstrate the involvement of mSin3A in the regulation of diverse pathways governing many aspects of normal and neoplastic growth and survival and provide an experimental framework for the analysis of essential genes with diverse biological functions.

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