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: 5.04). 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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    ABSTRACT: Background Transcriptional hotspots are defined as genomic regions bound by multiple factors. They have been identified recently as cell type specific enhancers regulating developmentally essential genes in many species such as worm, fly and humans. The in-depth analysis of hotspots across multiple cell types in same species still remains to be explored and can bring new biological insights.ResultsWe therefore collected 108 transcription-related factor (TF) ChIP sequencing data sets in ten murine cell types and classified the peaks in each cell type in three groups according to binding occupancy as singletons (low-occupancy), combinatorials (mid-occupancy) and hotspots (high-occupancy). The peaks in the three groups clustered largely according to the occupancy, suggesting priming of genomic loci for mid occupancy irrespective of cell type. We then characterized hotspots for diverse structural functional properties. The genes neighbouring hotspots had a small overlap with hotspot genes in other cell types and were highly enriched for cell type specific function. Hotspots were enriched for sequence motifs of key TFs in that cell type and more than 90% of hotspots were occupied by pioneering factors. Though we did not find any sequence signature in the three groups, the H3K4me1 binding profile had bimodal peaks at hotspots, distinguishing hotspots from mono-modal H3K4me1 singletons. In ES cells, differentially expressed genes after perturbation of activators were enriched for hotspot genes suggesting hotspots primarily act as transcriptional activator hubs. Finally, we proposed that ES hotspots might be under control of SetDB1 and not DNMT for silencing.Conclusion Transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes. In ES cells, they are predicted to act as transcriptional activator hubs and might be under SetDB1 control for silencing.
    BMC Bioinformatics 12/2014; 15(1):6591. DOI:10.1186/s12859-014-0412-0 · 2.67 Impact Factor
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    ABSTRACT: In the developing central nervous system (CNS), progenitor cells differentiate into progeny to form functional neural circuits. Radial glial cells (RGs) are a transient progenitor cell type that is present during neurogenesis. It is thought that a combination of neural trophic factors, neurotransmitters and electrical activity regulates the proliferation and differentiation of RGs. However, it is less clear how epigenetic modulation changes RG proliferation. We sought to explore the effect of histone deacetylase (HDAC) activity on the proliferation of RGs in the visual optic tectum of Xenopus laevis. We found that the number of BrdU-labeled precursor cells along the ventricular layer of the tectum decrease developmentally from stage 46 to stage 49. The co-labeling of BrdU-positive cells with brain lipid-binding protein (BLBP), a radial glia marker, showed that the majority of BrdU-labeled cells along the tectal midline are RGs. BLBP-positive cells are also developmentally decreased with the maturation of the brain. Furthermore, HDAC1 expression is developmentally down-regulated in tectal cells, especially in the ventricular layer of the tectum. Pharmacological blockade of HDACs using Trichostatin A (TSA) or Valproic acid (VPA) decreased the number of BrdU-positive, BLBP-positive and co-labeling cells. Specific knockdown of HDAC1 by a morpholino (HDAC1-MO) decreased the number of BrdU- and BLBP-labeled cells and increased the acetylation level of histone H4 at lysine 12 (H4K12). The visual deprivation-induced increase in BrdU- and BLBP-positive cells was blocked by HDAC1 knockdown at stage 49 tadpoles. These data demonstrate that HDAC1 regulates radial glia cell proliferation in the developing optical tectum of Xenopus laevis.
    PLoS ONE 03/2015; 10(3):e0120118. DOI:10.1371/journal.pone.0120118 · 3.53 Impact Factor
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    ABSTRACT: Inhibition of histone deacetylase (HDAC) is a promising strategy for cancer treatment. In this study, HDAC inhibitory activity of 15 Valencia-type peanut testa extracts was assessed in mammalian cell model. Nine of 15 testa extracts exhibited HDAC inhibitory activity. Two peanut testa extracts (genotypes ICG15042 and KK4) possessing the greatest HDAC inhibitory activity could inhibit the growth of all five human cancer cell lines tested. At 72-h treatment, both ICG15042 and KK4 testa extracts showed the most effective growth inhibition on Jurkat T-leukemia cells with IC50 values of 28.81 and 30.00 μg/mL, respectively. Both extracts were more toxic against the cancerous cell lines, but safer toward a noncancer cell line. Growth inhibitory effects of both extracts appeared to be mediated by induction of apoptosis in a dose-dependent manner. Moreover, some phenolic acids including protocatechuic, syringic, p-coumaric, ferulic and sinapinic acids, which may underpin their anticancer activity, were also identified and analyzed quantitatively.Practical ApplicationsHDAC inhibitory potentials of phenolic-rich testa extracts of 15 Valencia-type peanut genotypes in mammalian cell model were evaluated. The results suggest that peanut skins (testae) of nine peanut genotypes possessed HDAC inhibitory activity and two of them (ICG15042 and KK4), with the highest HDAC inhibitory activity, could inhibit cancer cell growth via apoptosis induction. Accordingly, peanut skins could be useful for application in areas such as alternative medicine for cancer treatment and functional food for dietary prevention of cancer.
    Journal of Food Biochemistry 04/2015; DOI:10.1111/jfbc.12128 · 0.85 Impact Factor

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