Co-repressor, co-activator and general transcription factor: the many faces of the Sin3 histone deacetylase (HDAC) complex

Abstract

At face value, the Sin3 histone deacetylase (HDAC) complex appears to be a prototypical co-repressor complex, that is, a multi-protein complex recruited to chromatin by DNA bound repressor proteins to facilitate local histone deacetylation and transcriptional repression. While this is almost certainly part of its role, Sin3 stubbornly refuses to be pigeon-holed in quite this way. Genome-wide mapping studies have found that Sin3 localises predominantly to the promoters of actively transcribed genes. While Sin3 knockout studies in various species result in a combination of both up- and down-regulated genes. Furthermore, genes such as the stem cell factor, Nanog, are dependent on the direct association of Sin3 for active transcription to occur. Sin3 appears to have properties of a co-repressor, co-activator and general transcription factor, and has thus been termed a co-regulator complex. Through a series of unique domains, Sin3 is able to assemble HDAC1/2, chromatin adaptors and transcription factors in a series of functionally and compositionally distinct complexes to modify chromatin at both gene-specific and global levels. Unsurprisingly, therefore, Sin3/HDAC1 have been implicated in the regulation of numerous cellular processes, including mammalian development, maintenance of pluripotency, cell cycle regulation and diseases such as cancer.

Keywords: chromatin; deacetylase; histone; transcription.

Figure 1.. Schematic of Sin3A/HDAC1 complex.

(A) Numbers indicate PAH domains 1–3. HID, HDAC-interaction domain; Sin3a_C, Sin3A C-terminal domain. Transcription factor (red) binding to Sin3A occurs predominantly via PAH1 and 2 as indicated. Chromatin-associated proteins are coloured orange and enzymes in green. (B) NMR structures of isolated PAH domains bound to the SID of the indicated factor. PAH domains are shown in blue, SIDs in red and HID in purple. All data were taken from the Protein Data Bank (PDB code indicated in brackets), SAP25:PAH1 (2RMS), REST:PAH1 (Sin3B, 2CZY), Mxd1:PAH2 (1G1E), HBP1:PAH2 (1S5R), Sap30:PAH3 (2LD7) and Suds3:HID (2N2H). (C) Sin3 may be subdivided into two major complexes — Sin3L/Rpd3L (L — large) and Sin3S/Rpd3S (small). In vivo, the Sin3A complex forms the scaffold of the larger Sin3L/Rpd3L complex, while Sin3B fulfils the same role in the Sin3S/Rpd3S complex. * OGT binds to both Tet1 and Sin3A. ** Pf1 has two SID domains. Pf1 SID2 (PHD2) binds to PAH1, while SID1 (PHD1) can interact with both MRG15 and PAH2 in a manner that is mutually exclusive. *** Arid4A (RBP1) can associate with Sin3 via Sap30 [85], while binding of Arid4B (Sap180) was mapped to the HID [38].

Figure 2.. Representation of the physiological roles of Sin3 complexes in mammalian cells and tissue development.

Inner ring represents the cellular process, with the outer rings denoting the specific complex functions. Processes in which Sin3A (blue), Sin3B (green) or both (orange) have been implicated are indicated.