HDAC3 is essential for DNA replication in hematopoietic progenitor cells

Summers, Alyssa R.; Fischer, Melissa A.; Stengel, Kristy R.; Zhao, Yue; Kaiser, Jonathan F.; Wells, Christina E.; Hunt, Aubrey; Bhaskara, Srividya; Luzwick, Jessica W.; Sampathi, Shilpa; Chen, Xi; Thompson, Mary Ann; Chen, David; Hiebert, Scott W.

doi:10.1172/jci60806

Cited by 76 publications

(106 citation statements)

References 59 publications

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“…While deletion of Hdac3 in Tregs led to increased expression of genes that were unaffected when HDAC3 was deleted in other cell types ( Figure 9F), for the most part there were similar changes in gene expression ( Figure 9G), as was reported for Hdac3 deletion in nonlymphoid cells (33)(34)(35)(36)(37)(38)(39)41). Overall, Hdac3 deletion led to altered expression of a wide variety of genes in Tregs, including those promoting activation of NF-κB and other proinflammatory pathways.…”

Section: Osteo-chondroprogenitor Cells (37) Hippocampal Cells (38) supporting

confidence: 67%

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Wang¹,

Liu²,

Han³

et al. 2015

J. Clin. Invest.

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Section: Osteo-chondroprogenitor Cells (37) Hippocampal Cells (38) supporting

confidence: 67%

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Wang¹,

Liu²,

Han³

et al. 2015

J. Clin. Invest.

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“…While such general changes in chromatin architecture may play a role in the generation of replication stress after HDAC inhibition, disruption of HDAC functions may also directly affect replication, as very short treatment with histone deacetylase inhibitors (HDIs) still generated robust reductions in the rates of replication fork progression (112,128). In cutaneous T-cell lymphoma (CTCL) cell lines treated with both broad-spectrum and HDAC3-selective inhibitors, the effects of HDI treatment on replication fork velocity were observed before the accumulation of global increases in histone acetylation (128).…”

Section: Figmentioning

confidence: 99%

“…Finally, it is likely that HDAC functions in replication control and maintenance of genome stability contributes to the phenotypes observed in mouse deletion models. For instance, replication stress was recently observed in a model of Hdac3 deletion in hematopoietic stem cells (112).…”

Section: Hdis Alter Gene Expression But Is It Important?mentioning

confidence: 99%

Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy

Stengel

Hiebert

2015

Antioxidants & Redox Signaling

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Significance: The contribution of epigenetic alterations to cancer development and progression is becoming increasingly clear, prompting the development of epigenetic therapies. Histone deacetylase inhibitors (HDIs) represent one of the first classes of such therapy. Two HDIs, Vorinostat and Romidepsin, are broad-spectrum inhibitors that target multiple histone deacetylases (HDACs) and are FDA approved for the treatment of cutaneous T-cell lymphoma. However, the mechanism of action and the basis for the cancer-selective effects of these inhibitors are still unclear. Recent Advances: While the anti-tumor effects of HDIs have traditionally been attributed to their ability to modify gene expression after the accumulation of histone acetylation, recent studies have identified the effects of HDACs on DNA replication, DNA repair, and genome stability. In addition, the HDIs available in the clinic target multiple HDACs, making it difficult to assign either their anti-tumor effects or their associated toxicities to the inhibition of a single protein. However, recent studies in mouse models provide insights into the tissue-specific functions of individual HDACs and their involvement in mediating the effects of HDI therapy. Critical Issues: Here, we describe how altered replication contributes to the efficacy of HDAC-targeted therapies as well as discuss what knowledge mouse models have provided to our understanding of the specific functions of class I HDACs, their potential involvement in tumorigenesis, and how their disruption may contribute to toxicities associated with HDI treatment. Future Directions: Impairment of DNA replication by HDIs has important therapeutic implications. Future studies should assess how best to exploit these findings for therapeutic gain. Antioxid. Redox Signal. 23, 51-65.

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“…have ventricular dysfunction that elevates intracardiac pressure on the thinner-walled atrium, which induces chronic inflammation and, in turn, structural remodeling and a predisposition to sustained AF. HDACs, in particular class I HDACs, promote the maturation of adipocytes and inflammatory cells that produce inflammatory cytokines (Haberland et al, 2010;Summers et al, 2013). In our dog model, we could assess not only atrial and circulating levels of TNFa and interleukins but also their cardiac production, which increased during AF and was mostly normalized by CI-994.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, only mature immune cells and adipocytes release inflammatory cytokines, and class I histone deacetylases (HDACs) promote the differentiation and maturation of these cell types (Haberland et al, 2010;Yamaguchi et al, 2010;Summers et al, 2013). We previously showed that the pan-histone deacetylase inhibitor trichostatin A reverses established atrial fibrosis and inducible atrial arrhythmias, without affecting cardiac chamber size, function, or hemodynamics in transgenic mice overexpressing the transcription factor homeodomain-only protein (Hopx Tg ), a model of ventricular hypertrophy (Liu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

Seki

LaCanna

Powers

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Current therapies are less effective for treating sustained/permanent versus paroxysmal atrial fibrillation (AF). We and others have previously shown that histone deacetylase (HDAC) inhibition reverses structural and electrical atrial remodeling in mice with inducible, paroxysmal-like AF. Here, we hypothesize an important, specific role for class I HDACs in determining structural atrial alterations during sustained AF. The class I HDAC inhibitor N-acetyldinaline [4-(acetylamino)-N-(2-aminophenyl) benzamide] (CI-994) was administered for 2 weeks (1 mg/kg/day) to Hopx transgenic mice with atrial remodeling and inducible AF and to dogs with atrial tachypacing-induced sustained AF. Class I HDAC inhibition prevented atrial fibrosis and arrhythmia inducibility in mice. Dogs were divided into three groups: 1) sinus rhythm, 2) sustained AF plus vehicle, and 3) sustained AF plus CI-994. In group 3, the time in AF over 2 weeks was reduced by 30% compared with group 2, along with attenuated atrial fibrosis and intra-atrial adipocyte infiltration. Moreover, group 2 dogs had higher atrial and serum inflammatory cytokines, adipokines, and atrial immune cells and adipocytes compared with groups 1 and 3. On the other hand, groups 2 and 3 displayed similar left atrial size, ventricular function, and mitral regurgitation. Importantly, the same histologic alterations found in dogs with sustained AF and reversed by CI-994 were also present in atrial tissue from transplanted patients with chronic AF. This is the first evidence that, in sustained AF, class I HDAC inhibition can reduce the total time of fibrillation, atrial fibrosis, intra-atrial adipocytes, and immune cell infiltration without significant effects on cardiac function.

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HDAC3 is essential for DNA replication in hematopoietic progenitor cells

Cited by 76 publications

References 59 publications

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

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