Determinants of epigenetic resistance to HDAC inhibitors in dystrophic fibro-adipogenic progenitors.
Determinants of epigenetic resistance to HDAC inhibitors in dystrophic fibro-adipogenic progenitors.
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DOI：
10.15252/embr.202254721
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发表时间：
2022-06-07
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影响因子：
7.7
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用组蛋白脱乙酰酶抑制剂(HDACi)治疗Duchenne肌营养不良症(DMD)的药物治疗目前正在进行临床试验；然而，临床前研究表明，HDACi的益处仅限于疾病的早期阶段。我们发现，晚期MDX小鼠的FAP表现出异常的HDAC活性和全基因组组蛋白乙酰化的变化，而HDACi并不能完全逆转这些变化。特别是，细胞周期激活和进展所需基因的启动子H3K27和/或H3K9/14的组合低乙酰化以及糖酵解与它们在晚期MDX FAP中的下调有关。这些改变不能被HDACi逆转，因为HDACi对HDACi诱导的H3K9/14超乙酰化具有普遍的抵抗力。相反，衰老相关分泌表型(SASP)基因启动子上的H3K9/14高乙酰化与其在晚期MDX FAP中的表达上调有关；然而，HDACi可以减少启动子乙酰化并钝化SASP基因的激活。这些数据表明，在DMD进展过程中，FAP通过表观遗传学上不同的和药物上可分离的事件发展出使人想起细胞衰老的疾病相关特征。他们还表明，HDACi可能在DMD的晚期保留了抗纤维化的作用。Duchenne肌营养不良模型小鼠成纤维脂肪祖细胞中HDAC活性的逐渐增加导致了与疾病晚期衰老相关的组蛋白乙酰化特征的改变，这种改变不能被HDAC抑制剂完全逆转。
Pharmacological treatment of Duchenne muscular dystrophy (DMD) with histone deacetylase inhibitors (HDACi) is currently being tested in clinical trials; however, pre‐clinical studies indicated that the beneficial effects of HDACi are restricted to early stages of disease. We show that FAPs from late‐stage mdx mice exhibit aberrant HDAC activity and genome‐wide alterations of histone acetylation that are not fully reversed by HDACi. In particular, combinatorial H3K27 and/or H3K9/14 hypo‐acetylation at promoters of genes required for cell cycle activation and progression, as well as glycolysis, are associated with their downregulation in late‐stage mdx FAPs. These alterations could not be reversed by HDACi, due to a general resistance to HDACi‐induced H3K9/14 hyperacetylation. Conversely, H3K9/14 hyper‐acetylation at promoters of Senescence Associated Secretory Phenotype (SASP) genes is associated with their upregulation in late‐stage mdx FAPs; however, HDACi could reduce promoter acetylation and blunt SASP gene activation. These data reveal that during DMD progression FAPs develop disease‐associated features reminiscent of cellular senescence, through epigenetically distinct and pharmacologically dissociable events. They also indicate that HDACi might retain anti‐fibrotic effects at late stages of DMD. Progressive increase of HDAC activity in Fibro‐adipogenic progenitors from Duchenne Muscular Dystrophy model mice leads to altered histone acetylation profiles associated with senescence at late disease stages that are not fully reversed by HDAC inhibitors.