mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival

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.[Keywords: Histone modifications; knock-out; mSin3 complex; mSin3A; transcriptional regulation; tumorigenesis] Supplemental material is available at http://www.genesdev.org.

Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53

“…By contrast, mSin3A heterozygosity does not promote tumorigenesis. This is consistent with the absence of aneuploidy detected upon mSin3A acute depletion (Dannenberg et al, 2005). The molecular mechanism by which mSds3 prevents aneuploidy remains an area of active investigation.…”

“…with the known mSin3/HDAC-directed deacetylation and activation of p53 (Kuzmichev et al, 2002;Dannenberg et al, 2005), we speculate that Sds3 haploinsufficiency reduces overall mSin3/HDAC activity and enhances the specific activity of p53 in p53 þ /À mice.…”

“…Of relevance to this study, loss of mSin3A, another essential component of the mSin3 complex, did not result in aneuploidy, indicating a specific role for mSds3 in maintaining accurate chromosomal segregation (Dannenberg et al, 2005). Many aspects of mSds3 biology touch on processes central to the development or suppression of cancer, including its roles in the proper segregation of chromosomes and the maintenance of mSin3-associated HDAC enzymatic activity.…”

“…Similar to Sds3 nullizygosity, the complete loss of mSin3A function is associated with a cell lethal condition and early embryonic lethality (Cowley et al, 2005;Dannenberg et al, 2005). However, despite their close physical and functional interactions, one clear distinction between mSds3 and mSin3A is the dispensability of mSin3A in the maintenance of accurate chromosomal segregation during cell division (David et al, 2003;Cowley et al, 2005;Dannenberg et al, 2005). This distinction provided an opportunity to dissect further whether the cancer phenotype of mSds3 heterozygosity relates its role in chromosome segregation, in the maintenance of mSin3/HDAC complex activity, or both.…”

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

“…This highlights a possible role of mutations in KDR , MYC , SIN3B , NLRC4 genes for the formation of metastases in ONB. Interesting interactions may occur between products of these genes: MYC attaches to SIN3B, while p53 to the NLRC4 promoter [66, 67]. In turn, whole exome sequencing of another metastatic ONB recognized 8 candidate cancer genes: BRINP1 , CARD11 , CDKN2C , MEIS1 , MINK1 , PPP6C , TGFBR2 and TP53 [40].…”