Epigenetic regulation of osteoblastogenesis by blackcurrant fruit extracts in vitro and in vivo

Abstract Background: Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown. Methods: The methylation status of HAVCR2 and LGALS9 were detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanism of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR.Results: SUV39H1 up-regulates H3K9me3 expression at the DNMT3A promoter region, which in turn induced expression of DNMT3A in cervical cancer. In addition, the mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 at the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 cellular expression level. Conclusion: These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.

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Abstract 442: Epigenetic Regulation of Ezh2 in Direct Human Cardiac Reprogramming

Circulation Research ◽

10.1161/res.127.suppl_1.442 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Yang Zhou ◽

Yawen Tang ◽

Lianzhong Zhao ◽

Rui Lu ◽

Jianyi Zhang

Keyword(s):

Cardiovascular Disease ◽

Cell Fate ◽

Epigenetic Regulation ◽

Ectopic Expression ◽

The United States ◽

Inhibitory Effect ◽

Loss Of Function ◽

Lower Efficiency

Cardiovascular disease is still the leading cause of death in the United States. Due to the limited regenerative capacity of adult hearts, the damage caused by heart injury could not be reversed and often progressed into heart failure. In need of cardiovascular disease treatment, many therapies aimed at either cell transplantation or cell regeneration have been proposed. Direct reprogramming of somatic cells into induced cardiomyocytes (iCMs) is considered to be a promising strategy for regenerative medicine. The induction of cardiomyocytes from non-myocytes has been achieved efficiently via ectopic expression of reprogramming factors both in vitro and in vivo with mice models. However, as human cells are more resistant to the reprogramming process, the generation of human iCMs (hiCMs) has been restricted by the factor that using more complex cocktails generated only functionally immature cells with lower efficiency and longer conversion time. The inefficiency of hiCMs production called for the identification and elucidation of underlying species-specific regulatory mechanisms in human, and removal of the additional epigenetic barriers which might be damping the hiCMs reprogramming. Here, we identified a human-specific epigenetic barrier, Enhancer of zesta homolog 2 (EZH2), via an unbiased loss-of-function screening. With the knockdown of EZH2, the hiCM reprogramming efficiency was significantly increased, accompanied with profound repression of collagen and extracellular matrix genes, which are related to the formation of fibrosis. Consistently, Inhibition of EZH2 catalytic activity via small molecules promotes hiCM reprogramming, suggesting that EZH2’s inhibitory effect was mediated by epigenetic regulation of histone modifications. Therefore, our study revealed a previously unrecognized regulatory mechanism of human cardiac reprogramming, which allows us to overcome the fibroblast fate barriers and ease the cardiac cell fate conversion.

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Epigenetic regulation by polyphenols in diabetes and related complications

Mediterranean Journal of Nutrition and Metabolism ◽

10.3233/mnm-200489 ◽

2020 ◽

Vol 13 (4) ◽

pp. 289-310

Author(s):

Hammad Ullah ◽

Anna De Filippis ◽

Cristina Santarcangelo ◽

Maria Daglia

Keyword(s):

Epigenetic Regulation ◽

Growth And Development ◽

Polyphenolic Compounds ◽

Epigenetic Alterations ◽

Daily Diet ◽

Potential Efficacy ◽

Health And Disease ◽

Early Phases

Diabetes mellitus (DM) is a chronic metabolic disorder and one of the most challenging health problems worldwide. Left untreated, it may progress causing serious complications. Genetics, epigenetics, and environmental factors are known to play an overlapping role in the pathogenesis of DM. Growing evidence suggests the hypothesis that the environment induces changes in the early phases of growth and development, influencing health and disease in the adulthood through the alteration in genetic expression of an individual, at least in part. DNA methylation, histone modifications and miRNAs are three mechanisms responsible for epigenetic alterations. The daily diet contains a number of secondary metabolites, with polyphenols being highest in abundance, which contribute to overall health and may prevent or delay the onset of many chronic diseases. Polyphenols have the ability to alter metabolic and signaling pathways at various levels, such as gene expression, epigenetic regulation, protein expression and enzyme activity. The potential efficacy of polyphenolic compounds on glucose homeostasis has been evidenced from in vitro, in vivo and clinical studies. The present review is designed to focus on epigenetic regulation exerted by polyphenolic compounds in DM and their complications, as well as to summarize clinical trials involving polyphenols in DM.

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Paradoxical epigenetic regulation of XAF1 mediates plasticity towards adaptive resistance evolution in MGMT-methylated glioblastoma

Scientific Reports ◽

10.1038/s41598-019-50489-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Qiong Wu ◽

Anders E. Berglund ◽

Dapeng Wang ◽

Robert J. MacAulay ◽

James J. Mulé ◽

...

Keyword(s):

Epigenetic Regulation ◽

Patient Survival ◽

Methylation Status ◽

Gene Signature ◽

Mgmt Methylation ◽

Intrinsic Resistance ◽

Adaptive Resistance ◽

Resistance Evolution

Abstract Epigenetic regulation of O6-alkylguanine DNA alkyltransferase (MGMT) is surrogate of intrinsic resistance to temozolomide (TMZ). However, mechanisms associated with adaptive resistance evolution of glioblastoma (GBM) relative to MGMT methylation remain unclear. We hereby report a paradoxical yet translational epigenetic regulation of plasticity towards adaptive resistance in GBM. Based on an adaptive resistance model of GBM cells with differential MGMT methylation profiles, MGMT-hypermethylation enhanced genetic and phenotypic plasticity towards adaptive resistance to TMZ while MGMT hypomethylation limited plasticity. The resulting model-associated adaptive resistance gene signature negatively correlated with GBM patient survival. XAF1, a tumor suppressor protein, paradoxically emerged as a mediator of differential plasticities towards adaptive resistance to TMZ through epigenetic regulation. XAF1 promoted resistance both in-vitro and in-vivo. Furthermore, XAF1 expression negatively correlated with XAF1 promoter methylation status, and negatively correlate with GBM patient survival. Collectively, XAF1 appears to have a pradoxical yet translational role in GBM.

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METTL14 Suppresses Pyroptosis and Diabetic Cardiomyopathy by Down-Regulating TINCR lncRNA

10.21203/rs.3.rs-642694/v1 ◽

2021 ◽

Author(s):

Liping Meng ◽

Hui Lin ◽

Xingxiao Huang ◽

Jingfan Wen ◽

Shengjie Wu

Keyword(s):

Diabetic Cardiomyopathy ◽

Epigenetic Regulation ◽

Regulatory Mechanism ◽

Rat Tissues ◽

The Novel ◽

Qrt Pcr ◽

Rna Immunoprecipitation

Abstract Background: N6-methyladenosine (m6A) is one of the most important epigenetic regulation of RNAs, such as lncRNAs. However, the underlying regulatory mechanism of m6A in diabetic cardiomyopathy (DCM) is very limited. In this study, we sought to define the role of METTL14-mediated m6A modification in pyroptosis and DCM progression.Methods: DCM rat model was established and qRT-PCR, western blot and immunohistochemistry (IHC) were used to detect the expression of METTL14 and TINCR. Gain-and-loss functional experiments were performed to define the role of METTL14-TINCR-NLRP3 axis in pyroptosis and DCM. RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to verify the underlying interaction.Results: In vivo and in vitro studies showed that pyroptosis was tightly involved in DCM progression. METTL14 was downregulated in cardiomyocytes and hear tissues of DCM rat tissues. Functionally, METTL14 suppressed pyroptosis and DCM via downregulating lncRNA TINCR, which further decreased the expression of key pyroptosis-related protein, NLRP3. Mechanistically, METTL14 increased m6A methylation level of TINCR gene, resulting in its downregulation. Moreover, the m6A reader protein YTHDF2 was essential for m6A methylation and mediated the degradation of TINCR. Finally, TINCR positively regulated NLRP3 through increasing its mRNA stability.Conclusions: Our work revealed the novel role of METTL14-mediated m6A methylation and lncRNA regulation in pyroptosis and DCM, which could help extend our understanding the epigenetic regulation of pyroptosis in DCM progression.

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