Histone Acetylation and Deacetylation

Kemp, Melissa M.; Schroeder, Frederick A.; Wagner, Florence F.; Wang, Qiu; Holson, Edward B.

doi:10.1002/3527600906.mcb.201100036

Cited by 11 publications

(24 citation statements)

References 234 publications

(250 reference statements)

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“…At the amino acid level, human HDAC3 is 53% identical to human HDAC1, 52% identical to human HDAC2 and 34% identical to human HDAC8 [4]. As a result, developing highly potent and selective HDAC3 inhibitors, through a variety of design strategies, has proven more feasible than developing HDAC2 selective inhibitors and several examples have been reported in the literature, especially in the hydroxamic acid and ortho-aminoanilide families.…”

Section: Development Of Hdac3 Selective Inhibitorsmentioning

confidence: 97%

“…Its sequence homology to HDAC1 is 83% and their catalytic core domains are almost identical [4], which makes the development of HDAC2 (vs HDAC1) selective inhibitors highly challenging. However, HDACs 1 and 2 share less than 53% sequence homology to HDACs 3 and 8.…”

Section: Development Of Hdac2 Selective Inhibitorsmentioning

confidence: 99%

“…The Class IIb HDACs include HDACs 6 and 10 with HDAC6 being predominantly localized to the cytoplasm while little is known about the localization of HDAC10. The Class IIb HDACs uniquely contain two independently active and substrate specific catalytic domains and it is the N-terminal domain of HDAC6 that is responsible for the deacetylation of a-tubulin [4]. The Class IV HDAC is composed of a single enzyme, HDAC11, with little known about its function; however, it has been detected across a broad range of tissue types including heart, muscle, kidney and testes [5].…”

mentioning

confidence: 99%

“…Class IIa HDACs (4, 5, 7 and 9) display more tissue specific distribution and can translocate between the nucleus and cytoplasm. These enzymes display weak inherent catalytic activity and require higher order protein complexes, often containing HDAC3, to become catalytically competent deacetylases [4]. The Class IIb HDACs include HDACs 6 and 10 with HDAC6 being predominantly localized to the cytoplasm while little is known about the localization of HDAC10.…”

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confidence: 99%

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Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

et al. 2013

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Increasing evidence supports a role for epigenetic involvement in some of the neurobiological alterations observed in neurodegenerative and psychiatric disorders including schizophrenia. In particular, there is mounting evidence implicating dysfunction in acetylation status, a chromatin modification mediated in part by HDACs, as a possible contributing factor to certain facets of this debilitating disease. Additional data support the notion that small molecule inhibition of HDACs may provide therapeutic alternatives to treating many of the symptoms associated with schizophrenia, particularly cognitive deficits. However, the development of highly potent and selective inhibitors of the individual HDAC isoforms will be necessary to delineate the associated biological effects and test the feasibility of such an approach for this complex and chronically treated disease. Here, we summarize current evidence for the role of HDAC isoforms in schizophrenia and highlight the state of the art in developing selective inhibitors of these isoforms as a potential treatment for schizophrenia.

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Section: Development Of Hdac3 Selective Inhibitorsmentioning

confidence: 97%

Section: Development Of Hdac2 Selective Inhibitorsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

et al. 2013

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“…As represented in Fig. 2, HDACs associate and regulate the acetylation of specific substrates and/or can often interact as components of multiprotein complexes [7,8].…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

et al. 2013

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Lysine acetylation is an ancient, evolutionarily conserved, reversible post-translational modification. A multitude of diverse cellular functions are regulated by this dynamic modification, including energy and metabolism, protein folding, transcription, and translation. Gene expression can be manipulated through changes in histone acetylation status, and this process is controlled by the function of 2 opposing enzymes: histone acetyl transferases and histone deacetylases (HDACs). The zinc-dependent HDACs are a family of hydrolases that remove acetyl groups from lysines, and their function can be modulated by the action of small molecule ligands. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small molecule chemotypes. Structural biology has aided the development of potent, and in some cases highly isoformselective, inhibitors that have demonstrated utility in a number of neurological disease models. Continued development and characterization of highly optimized small molecule inhibitors of HDAC enzymes will help refine our understanding of their function and, optimistically, lead to novel therapeutic treatment alternatives for a host of neurological disorders.

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FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors

Schroeder

Chonde

Riley

et al. 2013

Neuroscience Letters

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The purpose of this work -the first of its kind -was to evaluate the impact of chronic selective histone deacetylase (HDAC) inhibitor treatment on brain activity using uptake of the radioligand 18 F-fluorodeoxyglucose and positron emission tomography ( 18 FDG-PET). HDAC dysfunction and other epigenetic mechanisms are implicated in diverse CNS disorders and animal research suggests HDAC inhibition may provide a lead toward developing improved treatment. To begin to better understand the role of the class I HDAC subtypes HDAC 1, 2 and 3 in modulating brain activity, we utilized two benzamide inhibitors from the literature, compound 60 (Cpd-60) and CI-994 which selectively inhibit HDAC 1 and 2 or HDACs 1,2 and 3, respectively. One day after the seventh treatment with Cpd-60 (22.5 mg/kg) or CI-994 (5 mg/kg), 18 FDG-PET experiments (n = 11-12 rats per treatment group) revealed significant, local changes in brain glucose utilization. These 2-17% changes were represented by increases and decreases in glucose uptake. The pattern of changes was similar but distinct between Cpd-60 and CI-994, supporting that 18 FDG-PET is a useful tool to examine the relationship between HDAC subtype activity and brain activity. Further work using additional selective HDAC inhibitors will be needed to clarify these effects as well as to understand how brain activity changes influence behavioral response.

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Histone Acetylation and Deacetylation

Cited by 11 publications

References 234 publications

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

Therapeutic Potential of Isoform Selective Hdac Inhibitors for the Treatment of Schizophrenia

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors

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