Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Rusty Montgomery, May 22, 2015
  • Source
    • "HDACs are a family of enzymes responsible for the regulation of histone deacetylation, which promote greater chromatin compaction making it inaccessible to the transcriptional machinery [5] [6]. HDACs are grouped into four classes and have been implicated in diverse biological processes including cellular function, differentiation, development, apoptosis, and synaptogenesis [7]. However, the roles of individual HDACs in brain function have only been addressed recently [4] [8] [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. There are currently no effective FDA-approved treatments for NPC, although in the last years the inhibition of Histone Deacetylases (HDACs) has emerged as a potential treatment for this disease. However, the molecular mechanisms that deregulate HDACs activity in NPC disease are unknown. Previously our group had shown that the proapoptotic tyrosine kinase c-Abl signaling is activated in NPC neurons. Here, we demonstrate that c-Abl activity increases HDAC2 levels inducing neuronal gene repression of key synaptic genes in NPC models. Results: Our data show that: i) HDAC2 levels and activity are increased in NPC neuronal models and in Npc1(-/-) mice; ii) inhibition of c-Abl or c-Abl deficiency prevents the increase of HDAC2 protein levels and activity in NPC neuronal models; iii) c-Abl inhibition decreases the levels of HDAC2 tyrosine phosphorylation; iv) treatment with methyl-β-cyclodextrin and Vitamin E decrease the activation of the c-Abl/HDAC2 pathway in NPC neurons; v) in vivo treatment with two c-Abl inhibitors prevents the increase of HDAC2 protein levels in the brain of Npc1(-/-) mice and, vi) c-Abl inhibition prevents HDAC2 recruitment to the promoter of neuronal genes, triggering an increase in their expression.. Conclusion: our data show the involvement of the c-Abl/HDAC2 signaling pathway in the regulation of neuronal gene expression in NPC neuronal models. Thus, inhibition of c-Abl could be a pharmacological target for preventing the deleterious effects of increased HDAC2 levels in NPC disease.
    Full-text · Article · Nov 2015 · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    No preview · Article · Sep 2015 · Critical reviews in food science and nutrition
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Apr 2015
Show more