Article

Negative and Positive Regulation of Gene Expression by Mouse Histone Deacetylase 1

Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, A-1030 Vienna, Austria.
Molecular and Cellular Biology (Impact Factor: 4.78). 12/2006; 26(21):7913-28. DOI: 10.1128/MCB.01220-06
Source: PubMed

ABSTRACT

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from core histones. Because of their capacity to induce local condensation of chromatin, HDACs are generally considered repressors of transcription. In this report, we analyzed the role of the class I histone deacetylase HDAC1 as a transcriptional regulator by comparing the expression profiles of wild-type and HDAC1-deficient embryonic stem cells. A specific subset of mouse genes (7%) was deregulated in the absence of HDAC1. We identified several putative tumor suppressors (JunB, Prss11, and Plagl1) and imprinted genes (Igf2, H19, and p57) as novel HDAC1 targets. The majority of HDAC1 target genes showed reduced expression accompanied by recruitment of HDAC1 and local reduction in histone acetylation at regulatory regions. At some target genes, the related deacetylase HDAC2 partially masks the loss of HDAC1. A second group of genes was found to be downregulated in HDAC1-deficient cells, predominantly by additional recruitment of HDAC2 in the absence of HDAC1. Finally, a small set of genes (Gja1, Irf1, and Gbp2) was found to require HDAC activity and recruitment of HDAC1 for their transcriptional activation. Our study reveals a regulatory cross talk between HDAC1 and HDAC2 and a novel function for HDAC1 as a transcriptional coactivator.

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    • "Thus, both the DNA sequence and local chromatin modification patterns control the recruitment of class I KDAC complexes to specific genomic regions. However, this conventional view of class I KDACs as silencing factors has been challenged during the past years by several studies showing that histone deacetylase activity is important for the activation of certain genes and that HDAC1 and HDAC2 preferentially associate with active genes (Clayton et al. 2006; Kidder and Palmer 2012; Wang et al. 2002, 2009; Zupkovitz et al. 2006). In a genome-wide ChIP-seq analysis in human CD4+ cells a positive correlation between HDAC1/HDAC2 binding, histone acetylation and transcription was discovered (Wang et al. 2009). "

    Full-text · Dataset · Apr 2014
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    • "In some cases, histone deacetylation also correlates with transcriptional activation (for reviews and specific examples see 5,6). These activities were revealed using global chromatin immunoprecipitation (ChIP)-on-chip DNA microarray assays [7-9], as well as by direct gene- specific analysis. For example, in budding yeast, activation of osmoregulated genes depends on histone deacetylation through the recruitment of the histone deacetylase Rpd3 by the mitogen-activated protein kinase (MAPK) Hog1 [10]. "
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    ABSTRACT: In budding yeasts, the histone deacetylase Rpd3 resides in two different complexes called Rpd3L (large) and Rpd3S (small) that exert opposing effects on the transcription of meiosis-specific genes. By introducing mutations that disrupt the integrity and function of either Rpd3L or Rpd3S, we show here that Rpd3 function is determined by its association with either of these complexes. Specifically, the catalytic activity of Rpd3S activates the transcription of the two major positive regulators of meiosis, IME1 and IME2, under all growth conditions and activates the transcription of NDT80 only during vegetative growth. In contrast, the effects of Rpd3L depends on nutrients; it represses or activates transcription in the presence or absence of a nitrogen source, respectively. Further, we show that transcriptional activation does not correlate with histone H4 deacetylation, suggesting an effect on a nonhistone protein. Comparison of rpd3-null and catalytic-site point mutants revealed an inhibitory activity that is independent of either the catalytic activity of Rpd3 or the integrity of Rpd3L and Rpd3S.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "Thus, both the DNA sequence and local chromatin modification patterns control the recruitment of class I KDAC complexes to specific genomic regions. However, this conventional view of class I KDACs as silencing factors has been challenged during the past years by several studies showing that histone deacetylase activity is important for the activation of certain genes and that HDAC1 and HDAC2 preferentially associate with active genes (Clayton et al. 2006; Kidder and Palmer 2012; Wang et al. 2002, 2009; Zupkovitz et al. 2006). In a genome-wide ChIP-seq analysis in human CD4+ cells a positive correlation between HDAC1/HDAC2 binding, histone acetylation and transcription was discovered (Wang et al. 2009). "
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    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.
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