Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
Biomedical Informatics and Systems Medicine, Justus Liebig University, Giessen, Germany.
Nat Commun. 2022 Jul 20;13(1):4184. doi: 10.1038/s41467-022-31798-z.
The NAD-dependent SIRT1-7 family of protein deacetylases plays a vital role in various molecular pathways related to stress response, DNA repair, aging and metabolism. Increased activity of individual sirtuins often exerts beneficial effects in pathophysiological conditions whereas reduced activity is usually associated with disease conditions. Here, we demonstrate that SIRT6 deacetylates H3K56ac in myofibers to suppress expression of utrophin, a dystrophin-related protein stabilizing the sarcolemma in absence of dystrophin. Inactivation of Sirt6 in dystrophin-deficient mdx mice reduced damage of myofibers, ameliorated dystrophic muscle pathology, and improved muscle function, leading to attenuated activation of muscle stem cells (MuSCs). ChIP-seq and locus-specific recruitment of SIRT6 using a CRISPR-dCas9/gRNA approach revealed that SIRT6 is critical for removal of H3K56ac at the Downstream utrophin Enhancer (DUE), which is indispensable for utrophin expression. We conclude that epigenetic manipulation of utrophin expression is a promising approach for the treatment of Duchenne Muscular Dystrophy (DMD).
NAD 依赖性 SIRT1-7 家族蛋白去乙酰化酶在与应激反应、DNA 修复、衰老和代谢相关的各种分子途径中发挥着至关重要的作用。单个 Sirtuins 的活性增加通常在病理生理条件下产生有益的影响，而活性降低通常与疾病状况有关。在这里，我们证明 SIRT6 在肌纤维中去乙酰化 H3K56ac 以抑制肌联蛋白的表达，肌联蛋白是一种与营养不良蛋白相关的蛋白，在没有营养不良蛋白的情况下稳定肌膜。在缺乏营养不良蛋白的 mdx 小鼠中敲除 Sirt6 减少了肌纤维的损伤，改善了肌营养不良的病理，提高了肌肉功能，从而减弱了肌肉干细胞（MuSCs）的激活。ChIP-seq 和使用 CRISPR-dCas9/gRNA 方法的特定基因座招募 SIRT6 表明，SIRT6 对于去除下游肌联蛋白增强子（DUE）处的 H3K56ac 至关重要，这对于肌联蛋白的表达是必不可少的。我们得出结论，对肌联蛋白表达的表观遗传调控是治疗杜氏肌营养不良症（DMD）的一种有前途的方法。
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