scholarly journals Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

2017 ◽  
Vol 131 (15) ◽  
pp. 1841-1857 ◽  
Author(s):  
Zheng Xu ◽  
Qian Tong ◽  
Zhiguo Zhang ◽  
Shudong Wang ◽  
Yang Zheng ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Histone Deacetylases ◽  
Histone H3 ◽  
Gene Promoter ◽  
Pathological Examination ◽  
Total Histone ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
H3 Acetylation

Inhibition of total histone deacetylases (HDACs) was phenomenally associated with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to determine whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevents DCM. Type 1 diabetes OVE26 and age-matched wild-type (WT) mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 months. These mice were then killed immediately or 3 months later for cardiac function and pathological examination. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice killed immediately or 3 months later following the 3-month treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunoprecipitation (ChIP) assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. The present study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.

scholarly journals Neuroprotection by Histone Deacetylase-Related Protein

2006 ◽  
Vol 26 (9) ◽  
pp. 3550-3564 ◽  
Author(s):  
Brad E. Morrison ◽  
Nazanin Majdzadeh ◽  
Xiaoguang Zhang ◽  
Aaron Lyles ◽  
Rhonda Bassel-Duby ◽  
...  
Keyword(s):  
Cell Death ◽  
Histone Deacetylase ◽  
Neuronal Death ◽  
Histone Deacetylases ◽  
Essential Feature ◽  
Gene Promoter ◽  
Related Protein ◽  
Phosphatidylinositol 3 Kinase ◽  
Histone Deacetylase 1 ◽  
H3 Acetylation

ABSTRACT The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by forced expression of HDRP is not accompanied by activation of the phosphatidylinositol 3-kinase-Akt or Raf-MEK-ERK signaling pathway, and treatment with pharmacological inhibitors of these pathways fails to inhibit the neuroprotection by HDRP. Stimulation of c-Jun phosphorylation and expression, an essential feature of neuronal death, is prevented by HDRP. We found that HDRP associates with c-Jun N-terminal kinase (JNK) and inhibits its activity, thus explaining the inhibition of c-Jun phosphorylation by HDRP. HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter. Although HDRP lacks intrinsic deacetylase activity, treatment with pharmacological inhibitors of histone deacetylases induces apoptosis even in the presence of ectopically expressed HDRP, underscoring the importance of c-Jun promoter deacetylation by HDRP-HDAC1 in HDRP-mediated neuroprotection. Our results suggest that neuroprotection by HDRP is mediated by the inhibition of c-Jun through its interaction with JNK and HDAC1.

scholarly journals Early Enriched Environment Prevents Epigenetic p11 Gene Changes Induced by Adulthood Stress in Mice

2021 ◽  
Vol 22 (4) ◽  
pp. 1928
Author(s):  
Mi Kyoung Seo ◽  
Ah Jeong Choi ◽  
Dae-Hyun Seog ◽  
Jung Goo Lee ◽  
Sung Woo Park
Keyword(s):  
Early Life ◽  
Epigenetic Modification ◽  
Histone H3 ◽  
Gene Promoter ◽  
Postnatal Period ◽  
Enriched Environment ◽  
Positive Effects ◽  
Adult Mice ◽  
Underlying Mechanisms ◽  
H3 Acetylation

Positive experiences in early life may improve the capacity to cope with adulthood stress through epigenetic modification. We investigated whether an enriched environment (EE) in the postnatal period affected epigenetic changes in the p11 gene induced by chronic unpredictable stress (CUS) in adult C57BL/6J mice. EE was introduced for 5 weeks during postnatal days 21–55. After EE, the mice were subjected to CUS for 4 weeks. EE prevented depression-like behavior induced by adult CUS. EE prevented a decrease in p11 mRNA and histone H3 acetylation induced by CUS, with changes in the expression of histone deacetylase 5. Moreover, EE prevented changes in trimethylation of histone H3 lysine 4 (H3K4) and H3K27 induced by CUS. Furthermore, EE had positive effects on behavior and epigenetic alterations in adult mice without CUS. These results suggest that one of the underlying mechanisms of early-life EE may involve epigenetic modification of the hippocampal p11 gene promoter.

scholarly journals Reduced Histone H3 Acetylation in CD4+T Lymphocytes: Potential Mechanism of Latent Autoimmune Diabetes in Adults

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Xi-yu Liu ◽  
Jiang-feng Xu
Keyword(s):  
Gene Expression ◽  
T Lymphocytes ◽  
Histone Deacetylases ◽  
Autoimmune Diabetes ◽  
Histone H3 ◽  
Histone Acetyltransferases ◽  
Healthy Controls ◽  
Latent Autoimmune Diabetes ◽  
Histone H3 Acetylation ◽  
H3 Acetylation

Aims. Latent autoimmune diabetes in adults (LADA) is the result of gene-environment interactions. Histone acetylation regulates gene expression and maybe interpret how environmental factors modify LADA. Hence, we studied the histone acetylation patterns in CD4+T lymphocytes from LADA patients.Methods. Blood CD4+T lymphocytes from 28 patients with LADA and 28 healthy controls were obtained to detect histone H3 acetylation and H4 acetylation. The gene expression of histone acetyltransferases (P300 and CREBBP) and histone deacetylases (HDAC1, HDAC2, and HDAC7) was measured by real-time polymerase chain reaction (RT-PCR).Results. Compared to healthy controls, reduced global H3 acetylation was observed in LADA patients’ CD4+T lymphocytes (P<0.05). Global level of H4 acetylation was not statistically different. Among LADA, CD4+T lymphocytes H3 acetylation was associated with glycosylated hemoglobin (HbA1c) and GADA titer. Compared to healthy controls, the expression of histone acetyltransferases CREBBP in LADA patients was downregulated, and the expression of histone deacetylases HDAC1 and HDAC7 was upregulated.Conclusion. A concerted downregulation of histone H3 acetylation was found in CD4+T lymphocytes of LADA patients, and this might provide evidence of a novel epigenetic explanation for the pathogenesis of LADA and its complications.

OsHDA710-Mediated Histone Deacetylation Regulates Callus Formation of Rice Mature Embryo

2020 ◽  
Vol 61 (9) ◽  
pp. 1646-1660
Author(s):  
Haidao Zhang ◽  
Fu Guo ◽  
Peipei Qi ◽  
Yizi Huang ◽  
Yongyao Xie ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Callus Formation ◽  
Trichostatin A ◽  
Expression Patterns ◽  
Histone H3 ◽  
Mature Embryo ◽  
Histone Deacetylation ◽  
Auxin Response ◽  
Histone H3 Acetylation ◽  
H3 Acetylation

Abstract Histone deacetylases (HDACs) play important roles in the regulation of eukaryotic gene expression. The role of HDACs in specialized transcriptional regulation and biological processes is poorly understood. In this study, we evaluated the global expression patterns of genes related to epigenetic modifications during callus initiation in rice. We found that the repression of HDAC activity by trichostatin A (TSA) or by OsHDA710 mutation (hda710) results in impaired callus formation of rice mature embryo and increased global histone H3 acetylation levels. The HDAC inhibition decreased auxin response and cell proliferation in callus formation. Meanwhile, the transcriptional repressors OsARF18 and OsARF22 were upregulated in the callus of hda710. The chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) analysis demonstrated that the callus of hda710 exhibited enhanced histone H3 acetylation levels at the chromatin regions of OsARF18 and OsARF22. Furthermore, we found that OsARF18 and OsARF22 were regulated through OsHDA710 recruitment to their target loci. In addition, overexpression of OsARF18 decreased the transcription of downstream genes PLT1 and PLT2 and inhibited callus formation of the mature embryo. These results demonstrate that OsHDA710 regulates callus formation by suppressing repressive OsARFs via histone deacetylation during callus formation of rice mature embryo. This indicates that OsHDA710-mediated histone deacetylation is an epigenetic regulation pathway for maintaining auxin response during cell dedifferentiation.

scholarly journals Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Cristian Doñas ◽  
Macarena Fritz ◽  
Valeria Manríquez ◽  
Gabriela Tejón ◽  
María Rosa Bono ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Trichostatin A ◽  
Gene Promoter ◽  
Treg Cells ◽  
Specific Subset ◽  
Global Increase ◽  
And Function ◽  
H3 Acetylation

Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that thefoxp3gene promoter becomes hyperacetylated inin vitrodifferentiated Tregs compared to naïve CD4+T cells. We also show that the histone deacetylase inhibitor TSA stimulated thein vitrodifferentiation of naïve CD4+T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+Treg cells.

scholarly journals Association of the CpG Methylation Pattern of the Proximal Insulin Gene Promoter with Type 1 Diabetes

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e36278 ◽  
Author(s):  
Delphine Fradin ◽  
Sophie Le Fur ◽  
Clémence Mille ◽  
Nadia Naoui ◽  
Chris Groves ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gene Promoter ◽  
Methylation Pattern ◽  
Cpg Methylation ◽  
Insulin Gene
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