Modulating epigenetic HAT activity for reinstating acetylation homeostasis: A promising therapeutic strategy for neurological disorders

Ganai, Shabir Ahmad; Banday, Shahid; Farooq, Zeenat; Altaf, Mohammad

doi:10.1016/j.pharmthera.2016.07.001

Cited by 49 publications

(20 citation statements)

References 205 publications

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“…Significant reduction of H2BK120ub in Phf6 KO ESCs allowed us to check for potential crosstalk between H2BK120ub and H2BK12Ac. Given that CBP/p300 functions as an acetyltransferase of several lysine residues of histone H2B including K12 ( 55 ), we knocked down p300 or CBP by siRNA in WT and Phf6 KO ESCs with DOX treatment and checked whether knockdown of p300 or CBP affects H2BK120ub levels. Intriguingly, knockdown of p300 or CBP showed reduction of both H2BK120ub and H2BK12Ac levels with DOX treatment, indicating crosstalk between H2BK120ub and H2BK12Ac (Figure 4H ).…”

Section: Resultsmentioning

confidence: 99%

The chromatin-binding protein PHF6 functions as an E3 ubiquitin ligase of H2BK120 via H2BK12Ac recognition for activation of trophectodermal genes

Boo

Kim

et al. 2020

Nucleic Acids Research

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Epigenetic regulation is important for establishing lineage-specific gene expression during early development. Although signaling pathways have been well-studied for regulation of trophectoderm reprogramming, epigenetic regulation of trophectodermal genes with histone modification dynamics have been poorly understood. Here, we identify that plant homeodomain finger protein 6 (PHF6) is a key epigenetic regulator for activation of trophectodermal genes using RNA-sequencing and ChIP assays. PHF6 acts as an E3 ubiquitin ligase for ubiquitination of H2BK120 (H2BK120ub) via its extended plant homeodomain 1 (PHD1), while the extended PHD2 of PHF6 recognizes acetylation of H2BK12 (H2BK12Ac). Intriguingly, the recognition of H2BK12Ac by PHF6 is important for exerting its E3 ubiquitin ligase activity for H2BK120ub. Together, our data provide evidence that PHF6 is crucial for epigenetic regulation of trophectodermal gene expression by linking H2BK12Ac to H2BK120ub modification.

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Section: Resultsmentioning

confidence: 99%

The chromatin-binding protein PHF6 functions as an E3 ubiquitin ligase of H2BK120 via H2BK12Ac recognition for activation of trophectodermal genes

Boo

Kim

et al. 2020

Nucleic Acids Research

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“…Since HATs and HDACs represent master regulators of transcriptional events, the disruption of the carefully orchestrated interplay between acetylation and deacetylation events frequently results in the onset or progression of genetically driven diseases. HDACs have been thoroughly investigated and promoted as drug targets in cancer, neurological diseases, and immune disorders [8,9]. Hence, HDACs have been subject to extensive drug development efforts.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, there has been far less effort in the area of HAT inhibitors for therapeutic applications in epigenetic diseases. Various studies have implied HATs in the emergence or progression of diseases such as prostate cancer, colon cancer, and neurological disorders [9][10][11][12]. Consequently, these findings stimulated chemical probe development efforts with the goal of identifying highly potent inhibitors of HAT activity as well as high-affinity probes to study specific HAT functions and their diverse implications in disease.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Richters

Koehler

2017

CMC

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Histone acetyltransferases (HATs) are epigenetic drivers that catalyze the acetyl transfer from acetyl-CoA to lysines of both histone and non-histone substrates and thereby induce transcription either by chromatin remodeling or direct transcription factor activation. Histone deacetylases (HDACs) conduct the reverse reaction to counter HAT activity. Physiological processes such as cell cycle progression or apoptosis require a thoroughly balanced equilibrium of the interplay between acetylation and deacetylation processes to maintain or, if required, alter the global acetylome status. Aberrant HAT activity has recently been demonstrated to play a crucial role in the progression of various diseases such as prostate, lung, and colon cancers as well as glioblastomas and neurodegenerative diseases. Recent investigations have aimed for the identification of HAT modulators to further decipher the complexity of acetyl transferase related signaling cascades and discover potential leads for drug design approaches. HDACs have been extensively characterized and targeted by small molecules, including four FDA-approved HDAC inhibitors; in contrast, HATs have not been active targets for therapeutic development. This review will summarize the status of HAT associated diseases and the arsenal of currently known and available HAT inhibitors with respect to their discovery, further improvements, and current applications.

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“…Generally, antidepressants elicit their therapeutic effects only after chronic treatment and are not effective in all patients [Hyman and Nestler, 1996;Duman et al, 2016]. Altered HDAC expression affects learning, memory and mood related behaviors [Guan et al, 2009;Graff et al, 2014] while different HDAC expression patterns have been associated with bipolar disorder, major depressive disorder, schizophrenia, and neurodegeneration [Benes and Berretta, 2001;Sharma et al, 2008;Covington et al, 2009;Ganai et al, 2016]. Class I and II HDACs are modified in psychiatric diseases making these of interest as drug targets [Benes and Berretta, 2001;Covington et al, 2009;Hobara et al, 2010;Kurita et al, 2012].…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Epigenetic Mechanisms in Psychiatric Diseases and Epigenetic Therapy

Karslı-Çeppioğlu

2016

Drug Development Research

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Preclinical Research Epigenetic mechanisms refer covalent modification of DNA and histone proteins that control transcriptional regulation of gene expression. Epigenetic regulation is involved in the development of the nervous system and plays an important role in the pathophysiology of psychiatric disorders, including depression, bipolar disorder, and schizophrenia. Epigenetic drugs, including histone deacetylation and DNA methylation inhibitors have received increased attention for the management of psychiatric diseases. The purpose of this review is to discuss the potential of epigenetic drugs to treat these disorders and to clarify the mechanisms by which they regulate the dysfunctional genes in the brain. Drug Dev Res 77 : 407-413, 2016. © 2016 Wiley Periodicals, Inc.

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Modulating epigenetic HAT activity for reinstating acetylation homeostasis: A promising therapeutic strategy for neurological disorders

Cited by 49 publications

References 205 publications

The chromatin-binding protein PHF6 functions as an E3 ubiquitin ligase of H2BK120 via H2BK12Ac recognition for activation of trophectodermal genes

The chromatin-binding protein PHF6 functions as an E3 ubiquitin ligase of H2BK120 via H2BK12Ac recognition for activation of trophectodermal genes

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Epigenetic Mechanisms in Psychiatric Diseases and Epigenetic Therapy

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