Transcription - Sin3 and NuRD in transcription regulation

Sin3 and NuRD in transcription regulation

Activation and repression of gene expression correlate with the state of acetylation of the histones. In general, histone acetylation correlates with more open chromatin and active gene expression, whereas deacetylation correlates with closed chromatin and repressed gene expression. NuRD and Sin3 are two major class I histone deacetylase-containing complexes. These complexes play important roles in distinct aspects of embryonic and post-embryonic development [1], [2].

NuRD and Sin3 both contain Histone deacetylase class I, a complex that consists of Histone deacetylase 1 and 2 (Hdac1 and Hdac2), Retinoblastoma binding protein 4 and 7 (Rbbp4 and Rbbp7). In addition, NuRD may contain both GATA zinc finger domain containing 2A and 2B (p66alpha and p66beta). Metastasis associated 1, 2 and 3 (MTA1, MTA2 and MTA3) are mutually exclusive within NuRD, as are Methyl-CpG binding domain protein 2 and 3 (MBD2 or MBD3) [1], [2].

Sin3 complexes contain Suppressor of defective silencing 3 homolog (SDS3), AT rich interactive domain 4A and 4B (ARID4A and ARID4B), Sin3A-associated protein 18kDa, 30kDa and 130kDa (SAP18, SAP30 and SAP130) and either SIN3 homolog A (Sin3a) or SIN3 homolog B (Sin3b) [1], [2].

Sin3 complexes have also been shown to interact with a variety of developmentally important factors that are not directly involved in cell cycle control. For example, Sin3 recruitment is required for repression by RE1-silencing transcription factor (NRSF) [3], [4] that silences neuronal gene expression programmes in non-neuronal tissues [5] and fetal cardiac genes in adult cardiac myocytes [2], [6].

It has also been proposed that the unliganded nuclear hormone receptors Thyroid hormone receptor alpha (TR-alpha), Retinoic acid receptor alpha and beta (RAR-alpha and RAR-beta), Peroxisome proliferator-activated receptor alpha (PPAR-alpha) [7], [8], [9] and other transcription factors can repress their targets by recruiting co-repressor supercomplexes containing Sin3 and closely related co-repressors nuclear receptor co-repressor 1 and 2 (N-CoR and SMRT), Splicing factor proline/glutamine-rich (PSF) and Non-POU domain containing octamer-binding (NRB54) [2], [10].

References:

1. Ahringer J
   NuRD and SIN3 histone deacetylase complexes in development. Trends in genetics : TIG 2000 Aug;16(8):351-6
2. McDonel P, Costello I, Hendrich B
   Keeping things quiet: roles of NuRD and Sin3 co-repressor complexes during mammalian development. The international journal of biochemistry & cell biology 2009 Jan;41(1):108-16
3. Grimes JA, Nielsen SJ, Battaglioli E, Miska EA, Speh JC, Berry DL, Atouf F, Holdener BC, Mandel G, Kouzarides T
   The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. The Journal of biological chemistry 2000 Mar 31;275(13):9461-7
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   The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix. Journal of molecular biology 2005 Dec 9;354(4):903-15
5. Schoenherr CJ, Anderson DJ
   The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science (New York, N.Y.) 1995 Mar 3;267(5202):1360-3
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   The repressor element 1-silencing transcription factor regulates heart-specific gene expression using multiple chromatin-modifying complexes. Molecular and cellular biology 2007 Jun;27(11):4082-92
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   A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 1997 May 1;387(6628):43-8
8. Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT, Parks DJ, Moore JT, Kliewer SA, Willson TM, Stimmel JB
   Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature 2002 Feb 14;415(6873):813-7
9. Pile LA, Spellman PT, Katzenberger RJ, Wassarman DA
   The SIN3 deacetylase complex represses genes encoding mitochondrial proteins: implications for the regulation of energy metabolism. The Journal of biological chemistry 2003 Sep 26;278(39):37840-8
10. Mathur M, Tucker PW, Samuels HH
    PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors. Molecular and cellular biology 2001 Apr;21(7):2298-311