Disease relevance of Sin3a

• Pf1SID2 does not have sequence similarity with either Mad SID or Pf1SID1 and therefore represents a novel Sin3 binding domain [1].
• Heterozygous msin3A(+/-) mice with a systemic twofold decrease in mSin3A protein develop splenomegaly as well as kidney disease indicative of a disruption of lymphocyte homeostasis [2].
• From a developmental standpoint, a comparative analysis of Myc, Mxi1-SR and Sin3A expression during postnatal mouse development and in differentiating mouse erythroleukemia (MEL) cells revealed that dramatic and reciprocal changes in Myc and Mxi1-SR mRNA levels are accompanied by minimal stage-specific changes in mSin3A gene expression [3].

High impact information on Sin3a

• Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription [4].
• Gene-specific targeting of the Sin3 corepressor complex by DNA-bound repressors is an important mechanism of gene silencing in eukaryotes [5].
• Mad-mSin3 association requires PAH2 of mSin3A/mSin3B and the first 25 residues of Mad, which contains a putative amphipathic alpha-helical region [6].
• 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 [7].
• 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 [7].

Biological context of Sin3a

• The pattern of CoREST gene expression is more restricted, suggesting that mSin3A is required constitutively for REST repression, whereas CoREST is recruited for more specialized repressor functions [8].
• 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 [7].
• Pf1 has independent binding sites for MRG15 and mSin3A [9].
• In contrast, mSin3A nullizygous cells show normal chromosome dynamics and cytogenetic profiles [10].
• We conclude that Phe-7 is the critical determinant and provides the molecular specificity for the association between Sin3 and Mad in regulating cell growth and differentiation [11].

Anatomical context of Sin3a

• The mSin3A chromatin-modifying complex is essential for embryogenesis and T-cell development [2].
• In order to understand the role of mSin3A during development, we generated constitutive germ line as well as conditional msin3A deletions. msin3A deletion in the developing mouse embryo results in lethality at the postimplantation stage, demonstrating that it is an essential gene [2].
• This constant expression profile, coupled with the observation that over-expression of mSin3A does not augment the anti-Myc activity of Mxi1-SR in the rat embryo fibroblast (REF) transformation assay, suggests that mSin3A is not a limiting factor in the regulation of Myc superfamily function [3].

Associations of Sin3a with chemical compounds

• Here, we report that in retinal Müller cells, increased glycolytic flux causes increased methylglyoxal modification of the corepressor mSin3A [4].
• Consistent with this corepressor function, depletion of endogenous mSin3A by small interfering RNA was sufficient to enhance prolactin gene expression by 70%, comparable to the induction by the HDAC inhibitor, trichostatin A [12].
• However, in response to dopamine, histone deacetylase HDAC2 and corepressor mSin3A were rapidly recruited to the prolactin promoter, and association was sustained above basal levels over a 1-h period [12].

Physical interactions of Sin3a

• We have also found that both TEL and AML-1 interact with mSin3A [13].

Regulatory relationships of Sin3a

• The integral role of mSds3 in controlling chromosome segregation and mSin3-regulated transcriptional networks prompted efforts to determine the neoplastic impact of loss of one copy of mSds3 or mSin3A [10].
• Mutants of TEL that removed a binding site for the mSin3A corepressor but retained the ETS domain failed to repress stromelysin-1 [14].

Other interactions of Sin3a

• Association of the mSin3A-histone deacetylase 1/2 corepressor complex with the mouse steroidogenic acute regulatory protein gene [15].
• Furthermore, chromatin immunoprecipitation assays revealed Sp3, mSin3A, and HDAC1/2 association with the proximal region of the StAR promoter in situ [15].
• The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex [8].
• The inv(16) fusion protein was found in a ternary complex with AML-1 and mSin3A, suggesting that the inv(16) also acts by recruiting transcriptional corepressors and histone deacetylases [13].
• The mSin3A and N-CoR corepressors bind to the pointed domain and the central repression domain of TEL, respectively [16].

Analytical, diagnostic and therapeutic context of Sin3a

• Metabolic labeling and immunoprecipitation of mSin3A showed a marked increase in the synthesis of mSin3A protein in agreement with the immunoblotting results [17].

References