Haberland M, Montgomery RL, Olson EN.. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 10: 32-42

Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA.
Nature Reviews Genetics (Impact Factor: 36.98). 01/2009; 10(1):32-42. DOI: 10.1038/nrg2485
Source: PubMed


Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes, largely through their repressive influence on transcription. The expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programmes of gene expression. Recent analyses of HDAC knockout mice have revealed highly specific functions of individual HDACs in development and disease. Mutant mice lacking individual HDACs are a powerful tool for defining the functions of HDACs in vivo and the molecular targets of HDAC inhibitors in disease.

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    • "acetyltransferases (HATs) and histone deacetylases (HDACs) add and remove, respectively, acetyl groups while histone methyltransferases (HMTs) and histone demethylases (HDMs) add and remove methyl groups, respectively, from histone proteins (Haberland et al. 2009). "
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    ABSTRACT: Polyphenols are the most abundant phytochemicals in fruits, vegetables and plant-derived beverages. Recent findings suggest that polyphenols display the ability to reverse adverse epigenetic regulation involved in pathological conditions, such as obesity, metabolic disorder, cardiovascular and neurodegenerative diseases and various forms of cancer. Epigenetics, defined as heritable changes to the transcriptome, independent from those occurring in the genome, includes DNA methylation, histone modifications, and post transcriptional gene regulation by non-coding RNAs. Sinergistically and cooperatively these processes regulate gene expression by changing chromatin organization and DNA accessibility. Such induced epigenetic changes can be inherited during cell division, resulting in permanent maintenance of the acquired phenotype, but they may also occur throughout an individual life-course and may ultimately influence phenotypic outcomes (health and disease risk). In the last decade, a number of studies have shown that nutrients can affect metabolic traits by altering the structure of chromatin and directly regulate both transcription and translational processes. In this context, dietary polyphenol-targeted epigenetics becomes an attractive approach for disease prevention and intervention. Here, we will review how polyphenols, including flavonoids, curcuminoids and stilbenes, modulate the establishment and maintenance of key epigenetic marks, thereby influencing gene expression and, hence, disease risk and health.
    Critical reviews in food science and nutrition 09/2015; DOI:10.1080/10408398.2015.1062353 · 5.18 Impact Factor
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    • "TSA, originally isolated as a fungistatic antibiotic from Streptomyces platensis, was the first specific natural inhibitor described. Histone deacetylases play a key role in homeostasis of protein acetylation in histones and other proteins thus regulating fundamental cellular activities such as transcription and chromatin structure remodelling [20] [21]. TSA can interact with the catalytic site of histone deacetylase resulting in inactivation of this catalytic site and preventing the binding to its substrate [22] [23]. "
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    ABSTRACT: At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how chromatin structure affects this process and the sensitivity of DNA to DSB induction is still an unresolved question. Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to DSB-inducing agents such as ionizing radiation. This radiosensitivity is revealed with an enhancement of chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the heterochromatin, where they are less accessible. Besides, recently it has been reported that Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies chromatin structure. In order to study the impact of chromatin compaction on the chromosomal instability of A-T cells, the response to trichostatin-A, an histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on chromatin structure already in an open conformation. Differently, trichostatin-A post-treatment causing hyperacetylation of histone tails and reducing the heterochromatic DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that trichostatin-A post-treatment is favouring the slow component of DSB repair pathway, the one impaired in absence of a functionally ATM protein. Data obtained suggest a fundamental role of chromatin compaction on chromosomal instability in A-T cells.
    04/2015; 777:52-59. DOI:10.1016/j.mrfmmm.2015.04.009
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    • "Although global deletion of either Hdac1 or Hdac2 leads to a lethal phenotype (Lagger et al., 2002; Montgomery et al., 2007), demonstrating the unique roles of these two enzymes in early embryogenesis, redundancy of Hdac1 and Hdac2 function has been found in many somatic cell types (e.g. oligodendrocytes, Schwann cells, cardiomyocytes, basal cells and adipocytes) (Haberland et al., 2010; Jacob et al., 2011; LeBoeuf et al., 2010; Montgomery et al., 2007; Ye et al., 2009). In line with the previous studies, our results reveal that one allele of either Hdac1 or Hdac2 is sufficient to support normal kidney development, whereas loss of all four alleles leads to renal hypodysplasia and early postnatal lethality. "
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    ABSTRACT: Histone deacetylases (HDACs) regulate a broad range of biological processes through removal of acetyl groups from histones as well as non-histone proteins. Our previous studies showed that Hdac1 and Hdac2 are bound to promoters of key renal developmental regulators and that HDAC activity is required for embryonic kidney gene expression. However, the existence of many HDAC isoforms in embryonic kidneys raises questions concerning the possible specificity or redundancy of their functions. We report here that targeted deletion of both the Hdac1 and Hdac2 genes from the ureteric bud (UB) cell lineage of mice causes bilateral renal hypodysplasia. One copy of either Hdac1 or Hdac2 is sufficient to sustain normal renal development. In addition to defective cell proliferation and survival, genome-wide transcriptional profiling revealed that the canonical Wnt signaling pathway is specifically impaired in UB(Hdac1,2-/-) kidneys. Our results also demonstrate that loss of Hdac1 and Hdac2 in the UB epithelium leads to marked hyperacetylation of the tumor suppressor protein p53 on lysine 370, 379 and 383; these post-translational modifications are known to boost p53 stability and transcriptional activity. Genetic deletion of p53 partially rescues the development of UB(Hdac1,2-/-) kidneys. Together, these data indicate that Hdac1 and Hdac2 are crucial for kidney development. They perform redundant, yet essential, cell lineage-autonomous functions via p53-dependent and -independent pathways. © 2015. Published by The Company of Biologists Ltd.
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