Transcription and beyond: the role of mammalian class I lysine deacetylases

Abstract

The Rpd3-like members of the class I lysine deacetylase family are important regulators of chromatin structure and gene expression and have pivotal functions in the control of proliferation, differentiation and development. The highly related class I deacetylases HDAC1 and HDAC2 have partially overlapping but also isoform-specific roles in diverse biological processes, whereas HDAC3 and HDAC8 have unique functions. This review describes the role of class I KDACs in the regulation of transcription as well as their non-transcriptional functions, in particular their contributions to splicing, mitosis/meiosis, replication and DNA repair. During the past years, a number of mouse loss-of-function studies provided new insights into the individual roles of class I deacetylases in cell cycle control, differentiation and tumorigenesis. Simultaneous ablation of HDAC1 and HDAC2 or single deletion of Hdac3 severely impairs cell cycle progression in all proliferating cell types indicating that these class I deacetylases are promising targets for small molecule inhibitors as anti-tumor drugs.

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

“…Deletion of either Hdac1 or Hdac2 in a variety of tissues/cell types, including the heart, brain, endothelial cells, smooth muscle, and neural crest cells, ES cells, fibroblasts, B cells, thymocytes, keratinocytes, and various cell lines causes no or only mild effects. 9,16,28 Likewise, deletion of either Hdac1 or Hdac2 does not evoke an obvious effect on oocyte development to the full-grown oocyte stage. 43 Deletion of both Hdac1 and Hdac2, however, results in infertility due to oocyte development arresting at the secondary follicle stage, which is accompanied by mis-regulation of histone modifications, a significant reduction of global transcription, and an increased incidence of apoptosis.…”

“…The reader is referred to several excellent reviews discussing the physiological role of HDAC1 and HDAC2. 8,9,16,28,39 Here we summarize and discuss the results of experiments using conditional mutant mice in combination with RNA interference (RNAi) to dissect the roles of HDAC1 and HDAC2 in oocytes and preimplantation embryos.…”

“…29 Similarly, increased expression of P21 Cip1/Waf may contribute to the observed developmental delay from morula to blastocyst after depleting Hdac1 in preimplantation embryos, 42 suggesting a general function of HDAC1 in repressing the cyclin-dependent kinase inhibitor P21 and thus positively regulating cell cycle proliferation. 16 Indeed, the proliferation defect in embryonic stem cells is rescued by deleting P21. 79 Deleting both Hdac1 and Hdac2 in dividing cells results in a similar cell cycle block in G1 phase.…”

Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex

“…Histone deacetylases (HDACs) exhibit limited substrate specificity and rely on transcription factors with sequence-specific DNAbinding and/or chromatin-binding activities for their targeting specificity. Among 11 known Zn 2+ -dependent HDACs in mammals, only HDAC1, HDAC2, and HDAC3 are constitutively nuclear, regulating the transcription of a broad array of genes that impact fundamentally on cellular physiology and organism development (1)(2)(3). These HDACs are commonly found in multiprotein corepressor complexes, with the closely related HDAC1 and HDAC2 partitioning broadly into the Sin3L/Rpd3L, Sin3S/ Rpd3S, NuRD (nucleosome remodeling and deacetylase), and CoREST (corepressor of REST transcription factor) complexes, whereas HDAC3 is found exclusively in SMRT/NCoR (silencing mediator of retinoid and thyroid hormone receptor/nuclear receptor corepressor) complexes.…”

Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs

“…We cannot exclude, however, the importance of nonnuclear HDACs in modulating pancreatic recovery through the posttranslational regulation of nonhistone proteins. 49 VPA, however, primarily targets HDAC1 and other nuclear HDACs, and it does not appear to affect cytoplasmic HDACs. 50 The higher HDAC expression we observed during pancreatic recovery is similar to what was reported during pancreatic development by Haumaitre et al 16 They also found that HDACi shifted the expansion of pancreatic precursors in a rat embryonic explant from an acinar to b-cell phenotype, suggesting that HDACs play a role in the maturation of the embryonic precursors into acinar cells.…”