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Gene Review

Sin3a  -  transcriptional regulator, SIN3A (yeast)

Mus musculus

Synonyms: AW553200, Histone deacetylase complex subunit Sin3a, Kiaa4126, Paired amphipathic helix protein Sin3a, Sin3, ...
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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


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


Analytical, diagnostic and therapeutic context of Sin3a


  1. Pf1, a novel PHD zinc finger protein that links the TLE corepressor to the mSin3A-histone deacetylase complex. Yochum, G.S., Ayer, D.E. Mol. Cell. Biol. (2001) [Pubmed]
  2. The mSin3A chromatin-modifying complex is essential for embryogenesis and T-cell development. Cowley, S.M., Iritani, B.M., Mendrysa, S.M., Xu, T., Cheng, P.F., Yada, J., Liggitt, H.D., Eisenman, R.N. Mol. Cell. Biol. (2005) [Pubmed]
  3. Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression of the Myc antagonist Mxi1. Rao, G., Alland, L., Guida, P., Schreiber-Agus, N., Chen, K., Chin, L., Rochelle, J.M., Seldin, M.F., Skoultchi, A.I., DePinho, R.A. Oncogene (1996) [Pubmed]
  4. Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription. Yao, D., Taguchi, T., Matsumura, T., Pestell, R., Edelstein, D., Giardino, I., Suske, G., Ahmed, N., Thornalley, P.J., Sarthy, V.P., Hammes, H.P., Brownlee, M. Cell (2006) [Pubmed]
  5. Solution structure of the interacting domains of the Mad-Sin3 complex: implications for recruitment of a chromatin-modifying complex. Brubaker, K., Cowley, S.M., Huang, K., Loo, L., Yochum, G.S., Ayer, D.E., Eisenman, R.N., Radhakrishnan, I. Cell (2000) [Pubmed]
  6. Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Ayer, D.E., Lawrence, Q.A., Eisenman, R.N. Cell (1995) [Pubmed]
  7. mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival. Dannenberg, J.H., David, G., Zhong, S., van der Torre, J., Wong, W.H., Depinho, R.A. Genes Dev. (2005) [Pubmed]
  8. The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. Grimes, J.A., Nielsen, S.J., Battaglioli, E., Miska, E.A., Speh, J.C., Berry, D.L., Atouf, F., Holdener, B.C., Mandel, G., Kouzarides, T. J. Biol. Chem. (2000) [Pubmed]
  9. Role for the mortality factors MORF4, MRGX, and MRG15 in transcriptional repression via associations with Pf1, mSin3A, and Transducin-Like Enhancer of Split. Yochum, G.S., Ayer, D.E. Mol. Cell. Biol. (2002) [Pubmed]
  10. Haploinsufficiency of the mSds3 chromatin regulator promotes chromosomal instability and cancer only upon complete neutralization of p53. David, G., Dannenberg, J.H., Simpson, N., Finnerty, P.M., Miao, L., Turner, G.M., Ding, Z., Carrasco, R., Depinho, R.A. Oncogene (2006) [Pubmed]
  11. Molecular determinants of the interaction of Mad with the PAH2 domain of mSin3. Le Guezennec, X., Vriend, G., Stunnenberg, H.G. J. Biol. Chem. (2004) [Pubmed]
  12. Epigenetic mechanisms in the dopamine D2 receptor-dependent inhibition of the prolactin gene. Liu, J.C., Baker, R.E., Chow, W., Sun, C.K., Elsholtz, H.P. Mol. Endocrinol. (2005) [Pubmed]
  13. Mechanisms of transcriptional repression by the t(8;21)-, t(12;21)-, and inv(16)-encoded fusion proteins. Heibert, S.W., Lutterbach, B., Durst, K., Wang, L., Linggi, B., Wu, S., Wood, L., Amann, J., King, D., Hou, Y. Cancer Chemother. Pharmacol. (2001) [Pubmed]
  14. TEL, a putative tumor suppressor, modulates cell growth and cell morphology of ras-transformed cells while repressing the transcription of stromelysin-1. Fenrick, R., Wang, L., Nip, J., Amann, J.M., Rooney, R.J., Walker-Daniels, J., Crawford, H.C., Hulboy, D.L., Kinch, M.S., Matrisian, L.M., Hiebert, S.W. Mol. Cell. Biol. (2000) [Pubmed]
  15. Association of the mSin3A-histone deacetylase 1/2 corepressor complex with the mouse steroidogenic acute regulatory protein gene. Clem, B.F., Clark, B.J. Mol. Endocrinol. (2006) [Pubmed]
  16. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Wang, L., Hiebert, S.W. Oncogene (2001) [Pubmed]
  17. Expression of transcriptional repressor protein mSin3A but not mSin3B is induced during neuronal apoptosis. Korhonen, P., Tapiola, T., Suuronen, T., Salminen, A. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
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