Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression

Abstract

Histone deacetylases (HDACs) regulate gene expression by deacetylating histones and also modulate the acetylation of a number of nonhistone proteins, thus impinging on various cellular processes. Here, we analyzed the major class I enzymes HDAC1 and HDAC2 in primary mouse fibroblasts and in the B-cell lineage. Fibroblasts lacking both enzymes fail to proliferate in culture and exhibit a strong cell cycle block in the G1 phase that is associated with up-regulation of the CDK inhibitors p21 WAF1/CIP1 and p57 Kip2 and of the corresponding mRNAs. This regulation is direct, as in wild-type cells HDAC1 and HDAC2 are bound to the promoter regions of the p21 and p57 genes. Furthermore, analysis of the transcriptome and of histone modifications in mutant cells demonstrated that HDAC1 and HDAC2 have only partly overlapping roles. Next, we eliminated HDAC1 and HDAC2 in the B cells of conditionally targeted mice. We found that B-cell development strictly requires the presence of at least one of these enzymes: When both enzymes are ablated, B-cell development is blocked at an early stage, and the rare remaining pre-B cells show a block in G1 accompanied by the induction of apoptosis. In contrast, elimination of HDAC1 and HDAC2 in mature resting B cells has no negative impact, unless these cells are induced to proliferate. These results indicate that HDAC1 and HDAC2, by normally repressing the expression of p21 and p57, regulate the G1-to-S-phase transition of the cell cycle.[Keywords: Histone deacetylases; cell cycle control; p21; p57; B-cell development] Supplemental material is available at http://www.genesdev.org.

Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation

“…Of note, HDAC1 was reported to antagonize p53 via Sp1 in regulating p21 transcription (45). Furthermore, HDAC1 and HDAC2 act in concert to repress the expression of p21 and p57 and promote G1 to S phase progression in mouse embryonic fibroblasts in vitro and B cells in vivo (46).…”

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

“…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.…”

“…A similar situation is also observed recently in the developing nervous system, where a single allele of Hdac2, but not Hdac1, is sufficient for normal mouse brain development in the absence of its paralog. 38 Deletion of both Hdac1 and Hdac2 leads to DNA damage that ultimately results in apoptosis in a variety of cell types and tissues including B cells, 32 T cells, 34 thymocyte, 44 and brain. 38 A significant increased incidence of apoptosis accompanied by pronounced DNA damage is also observed in growing oocytes following loss of both Hdac1 and Hdac2 and likely attributed to hyperacetylation of TRP53.…”

“…39 Fibroblasts lacking both HDAC1 and HDAC2 fail to proliferate in culture and exhibit a strong cell cycle block in the G1 phase that is associated with upregulation of the CDK inhibitors p21 Cip1/Waf1 and p57 Kip2 . 32 Combined deletion of Hdac1 and Hdac2, or inactivation of their deacetylase activity in primary or oncogenic-transformed fibroblasts, results in a senescence-like G1 cell cycle arrest, accompanied by upregulation of the cyclin-dependent kinase inhibitor P21 and P53. 80 A similar situation is also observed in one-cell embryos; reduction in maternal Hdac1 combined with Hdac2 deficiency (Hdac1 − /+ /Hdac2 −/− ) in fertilized eggs results in developmental arrest from 1-cell to 2-cell transition due to a cell cycle block in G1.…”

Manipulation of B-cell responses with histone deacetylase inhibitors

“…Accumulating evidence has demonstrated that epigenetic changes play a key role in shaping gene expression profiles of differentiating lymphocytes 12,13 . Similarly, mice deficient in histone deacetylase (HDAC) enzymes 1 and 2 have disrupted B-cell development, survival and activation [14][15][16] . Therefore, pharmacological targeting of epigenetic enzymes such as HDACs arises as a potential method for manipulating antibody responses.…”