Multiple roles of class I HDACs in proliferation, differentiation, and development

Abstract

Class I Histone deacetylases (HDACs) play a central role in controlling cell cycle regulation, cell differentiation, and tissue development. These enzymes exert their function by deacetylating histones and a growing number of non-histone proteins, thereby regulating gene expression and several other cellular processes. Class I HDACs comprise four members: HDAC1, 2, 3, and 8. Deletion and/or overexpression of these enzymes in mammalian systems has provided important insights about their functions and mechanisms of action which are reviewed here. In particular, unique as well as redundant functions have been identified in several paradigms. Studies with small molecule inhibitors of HDACs have demonstrated the medical relevance of these enzymes and their potential as therapeutic targets in cancer and other pathological conditions. Going forward, better understanding the specific role of individual HDACs in normal physiology as well as in pathological settings will be crucial to exploit this protein family as a useful therapeutic target in a range of diseases. Further dissection of the pathways they impinge on and of their targets, in chromatin or otherwise, will form important avenues of research for the future.

Fig. 1

HDAC classification. The HDAC classes are indicated (class III HDACs—sirtuins—are not depicted). Blue rectangles depict the Deacetylase Domain (DAC), red rectangles indicate phosphorylation sites; Zinc finger (ZnF) and leucine rich motifs are also indicated. The numbers specify the number of amino acids

Fig. 2

Class I HDACs complexes and their components. a The Sin3 complex contains six subunits: the transcriptional co-repressor Sin3, two Sin3 associated proteins (SAP18 and 30) and two Rb associated proteins (RbAp46 and 48). HDAC1 and 2 form the catalytic core of this complex [115, 116]. b The Mi2/NuRD complex shares the dimers HDAC1 and 2 and RbAP46 and 48 with the Sin3 complex. In addition this complex contains the chromatin remodeler Mi2, the methyl CpG binding domain protein MBD2 or MBD3, the lysine-specific demethylase LSD1 [117], the transcriptional repressor p66 and MTA2 (a member of metastasis associated family) [–120]. c The CoREST complex contains the co-repressor CoREST, the lysine-specific demethylase LSD1, the Kruppel-like zinc-finger protein Znf217, the Sox-like protein and p80 [121]. d The N-CoR/SMRT complex contains N-CoR (Nuclear receptor CoRepressor) or SMRT (Silencing Mediator for Retinoid and Thyroid receptor), TBL1 (transducin β-like 1), TBLR1 (TBL related 1), GPS2 (G-protein pathway suppressor 2), the lysine-specific demethylase KDM4A [122] and HDAC3 ([123]; for review, see [12]). HDAC complexes are reviewed in [4, 13]

Fig. 3

HDAC1- and 2-mediated repression of cell cycle regulators. a Recruitment of HDAC1 and 2 complexes to their target genes by various transcription factors in different cellular systems. Transcription factors (TF) are schematized as gray circles and nucleosomes as yellow circles, cellular systems and target promoters are indicated; red inhibition symbols indicate direct repression by deacetylation of histones at the indicated loci. b Schematic representation of indirect repression of the p21 promoter by HADCs via p53 deacetylation