The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts

Abstract

HDACs (histone deacetylases) 1 and 2 are ubiquitous long-lived proteins, which are often found together in three major multiprotein co-repressor complexes: Sin3, NuRD (nucleosome remodelling and deacetylation) and CoREST (co-repressor for element-1-silencing transcription factor). Although there is a burgeoning number of non-histone proteins within the acetylome, these complexes contain multiple DNA/chromatin-recognition motifs, which, in combination with transcription factors, target HDAC1/2 to chromatin. Their physiological roles should therefore be viewed within the framework of chromatin manipulation. Classically, HDACs were thought to be recruited predominantly by transcriptional repressors to facilitate local histone deacetylation and transcriptional repression. More recently, genome-wide assays have mapped HDAC1/2 and their associated proteins to transcriptionally active loci and have provided alternative context-specific functions, whereby their repressive functions are subtly exerted to balance transcriptional activation and repression. With a few significant exceptions (early embryogenesis, brain development), HDAC1 and HDAC2 are functionally redundant. In most mouse knockout studies, deletion of both enzymes is required in order to produce a substantial phenotype. HDAC1/2 activity has been implicated in the development of numerous tissue and cell types, including heart, skin, brain, B-cells and T-cells. A common feature in all HDAC1/2-knockout, -knockdown and small-molecule inhibitor studies is a reduction in cell proliferation. A generic role in cell cycle progression could be exploited in cancer cells, by blocking HDAC1/2 activity with small-molecule inhibitors, making them potentially useful drug targets.

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.…”

“…Indeed, loss-of-function studies in mice provide important insights regarding the compensatory functions of HDAC1 and HDAC2 in regulating cell proliferation, apoptosis, and differentiation in different cell types and tissues. 8,28 Tissue-specific conditional knockout of Hdac1 or Hdac2 alone does not evoke an obvious phenotype in cardiomyocytes, 29 neuron precursors, 30 oligodendrocyte, 31 B cells, 32 embryonic epidermis, 33 and T cells, 34 whereas deletion of both genes results in severe phenotypes in all tissues examined. In contrast, results of other studies support the notion that HDAC1 and HDAC2 have distinct functions.…”

“…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.…”

Insights into Lysine Deacetylation of Natively Folded Substrate Proteins by Sirtuins

“…Notably, the residues 67 RRL 69 in PEPCK1 preceding Lys-70/Lys-71 form a ␤-strand as part of an antiparallel ␤-sheet. It needs further investigation whether the replacement of this sequence by the corresponding Ran sequence 34 EFE 36 confers Sirt2 activity or whether this is due to structural effects interfering with the formation of this ␤-sheet, maybe affecting the loops flexibility. IB, immunoblot.…”

“…A, Ran TFAcK37, TFAcK38, and TFAcK37/38 13-mer peptides bind to Sirt2 in the micromolar range as shown by isothermal titration calorimetry. 30 M Sirt2 (50 -356, non-His 6 -tagged) was titrated with 300 M trifluorolysine-acetylated Ran 13-mer peptide (Ran amino acids [31][32][33][34][35][36][37][38][39][40][41][42][43]. The reactions are all driven by a favorable reaction enthalpy, ⌬H, whereas the reaction of the TFAcK38 peptide is the only one driven by both favorable enthalpy and favorable entropy, T⌬S.…”