TFAM启动子的H3K4me3图谱改变导致2型糖尿病一级亲属前脂肪细胞的线粒体改变。

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-09-07 DOI:10.1186/s13148-023-01556-z
Michele Longo, Federica Zatterale, Rosa Spinelli, Jamal Naderi, Luca Parrillo, Pasqualina Florese, Cecilia Nigro, Alessia Leone, Augusta Moccia, Antonella Desiderio, Gregory A Raciti, Claudia Miele, Ulf Smith, Francesco Beguinot
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引用次数: 0

摘要

背景:2型糖尿病患者(FDR)的一级亲属患2型糖尿病(T2D)的风险很高,其皮下脂肪细胞肥大与肥胖无关。在FDR中,脂肪细胞异常导致早期胰岛素抵抗,并由脂肪细胞前体细胞(APC)早衰和脂肪生成途径募集受损决定。表观遗传学机制是脂肪细胞分化的信号,使我们假设异常的表观遗传学修饰会导致脂肪细胞功能障碍并增加T2D风险。为了验证这一假设,我们检测了健康FDR皮下脂肪组织APC中的全基因组组蛋白图谱。结果:测序数据分析显示,与线粒体相关基因显著富集的对照组(CTRL)相比,FDR中2644个区域的赖氨酸4三甲基化H3组蛋白(H3K4me3)差异富集。其中包括调节线粒体DNA(mtDNA)含量和稳定性的TFAM。在FDR-APC中,TFAM启动子处H3K4me3丰度的显著降低伴随着TFAM mRNA和蛋白质水平的降低。FDR-APC还表现出线粒体DNA含量和线粒体基因组转录的降低。同时,FDR-APC在脂肪生成过程中表现出分化受损和TFAM诱导。在CTRL APC中,TFAM siRNA降低mtDNA含量、线粒体转录和脂肪细胞分化,同时上调CDKN1A和ZMAT3衰老基因。此外,TFAM siRNA显著扩大了过氧化氢(H2O2)诱导的衰老,而H2O2不影响TFAM的表达。结论:组蛋白修饰调节APC在成熟细胞中的分化能力,至少部分是通过调节TFAM的表达和影响线粒体功能。TFAM启动子处H3K4me3富集减少会使人APC衰老和功能失调,增加T2D风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics.

Background: First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR.

Results: Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H2O2)-induced senescence, while H2O2 did not affect TFAM expression.

Conclusions: Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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