Role of histone and transcription factor acetylation in diabetes pathogenesis

Gray, Steven G.; Meyts, Pierre De

doi:10.1002/dmrr.559

Cited by 139 publications

(90 citation statements)

References 242 publications

(251 reference statements)

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“…In addition to histones, other proteins, including transcription factors such as NFκB, can be modified by acetylation/deacetylation [12,14]. NFκB acetylation leads to increased DNA-binding, enhanced transactivation and resistance to assembly with IκBα [12].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

et al. 2007

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Aims/hypothesis The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1β and IFNγ, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFκB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of proapoptotic genes. NFκB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. Materials and methods The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1β and IFNγ. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFκB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. Results HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1β induced a bi-phasic phosphorylation of inhibitor protein kappa Bα (IκBα) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IκBα degradation and NFκB DNA binding. Conclusions/interpretation HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFκB transactivating activity.

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Section: Introductionmentioning

confidence: 99%

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

et al. 2007

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“…Dysfunction of histone acetyltransferases and deacetylases is often associated with manifestation of several diseases including cancer, cardiac hypertrophy, asthma, and diabetes. [3][4][5] The most widely studied histone acetyltransferases (HATs), CBP (CREB binding protein)/ p300, are ubiquitously expressed global transcriptional coactivators, which play crucial roles in different cellular phenomenon including cell cycle control, differentiation, and apoptosis. 6 The transcriptional coactivator function of p300 is at least partially facilitated by its intrinsic HAT activity.…”

Section: Introductionmentioning

confidence: 99%

Activation of p300 Histone Acetyltransferase by Small Molecules Altering Enzyme Structure: Probed by Surface-Enhanced Raman Spectroscopy

et al. 2007

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Reversible acetylation of nucleosomal histones and nonhistone proteins play pivotal roles in the regulation of all the DNA templated phenomenon. Dysfunction of the enzymes involved in the acetylation/deacetylation leads to several diseases. Therefore, these enzymes are the targets for new generation therapeutics. Here, we report the synthesis of trifluoromethyl phenyl benzamides and their effect on histone acetyltransferase (HAT) activity of p300. One of these benzamides, CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), was discovered as a potent activator of the p300 HAT activity. We have found that pentadecyl hydrocarbon chain of CTPB is required to activate the HAT only under certain context. Furthermore, our results show that the relative position of -CF 3 and -Cl in CTB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide) is also very critical for the activation. Surface-enhanced Raman spectroscopy (SERS) of p300 and the HAT activator complexes evidently suggest that the activation of HAT activity is achieved by the alteration of p300 structure. Therefore, apart from elucidating the chemical basis for small molecule mediated activation of p300, this report also describes, for the first time, Raman spectroscopic analysis of the complexes of histone-modifying enzymes and their modulators, which may be highly useful for therapeutic applications.

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“…HAT and HDAC abnormalities have been associated with leukemia (14,15), diabetes (16) and other diseases of the immune system (17)(18)(19). The linkage of HAT and HDAC as components of a single complex permits dynamic responsiveness to extracellular stimulation (18,20).…”

mentioning

confidence: 99%

FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression

Samanta

Song

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

365

368

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The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repression by FOXP3 involves a histone acetyltransferase-deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9. The N-terminal 106 -190 aa of FOXP3 are required for TIP60 -FOXP3, HDAC7-FOXP3 association, as well as for the transcriptional repression of FOXP3 via its forkhead domain. FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo. Overexpression of TIP60 but not its histone acetyltransferase-deficient mutant promotes, whereas knockdown of endogenous TIP60 relieved, FOXP3-mediated transcriptional repression. A minimum FOXP3 ensemble containing native TIP60 and HDAC7 is necessary for IL-2 production regulation in T cells. Moreover, FOXP3 association with HDAC9 is antagonized by T cell stimulation and can be restored by the protein deacetylation inhibitor trichostatin A, indicating a complex dynamic aspect of T suppressor cell regulation. These findings identify a previously uncharacterized complex-based mechanism by which FOXP3 actively mediates transcriptional repression.A central theme that has emerged over the last 25 years is that a process of self-regulation of the immune response occurs to limit self-reactivity. Biochemical details of how the immune system distinguishes and regulates self and non-self remain to be fully documented (1). A recently characterized CD4 ϩ CD25 ϩ regulatory T cell subset expresses the Foxp3 transcription factor. As a transcriptional repressor of cytokine gene expression (2), Foxp3 was subsequently identified as an essential and sufficient regulator of natural regulatory T cell development and function (3-5).Mammalian transcriptional repressors can execute their function by either passive or active mechanisms (6, 7). FOXP3 may, for example, function as a passive transcriptional repressor in the case of its association with 9). In this study, we explore the role of FOXP3 as an active transcriptional repressor by revealing the dynamic FOXP3 ensemble formation with a specific histone acetyltransferase (HAT) and certain class II histone deacetylases (HDACs) in expanded human CD4 ϩ CD25 ϩ regulatory T cells (10, 11).Histone acetylation and histone deacetylation affect chromatin remodeling during T cell development and differentiation (12, 13). HAT and HDAC abnormalities have been associated with leukemia (14, 15), diabetes (16) and other diseases of the immune system (17-19). The linkage of HAT and HDAC as components of a single complex permits dynamic responsiveness to extracellular stimulation (18,20). The HAT TIP60 (Tat-interactive protein, 60 kDa), originally isolated as an HIV-1 TAT-interactive protein (21), functions as eith...

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Role of histone and transcription factor acetylation in diabetes pathogenesis

Cited by 139 publications

References 242 publications

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

Activation of p300 Histone Acetyltransferase by Small Molecules Altering Enzyme Structure: Probed by Surface-Enhanced Raman Spectroscopy

FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression

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