KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy
KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy
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DOI：
10.1038/s44161-023-00214-0
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发表时间：
2023-02
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影响因子：
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通讯作者：
Abdalla Ahmed;Jibran Nehal Syed;Lijun Chi;Yaxu Wang;C. Perez-Romero;Dorothy Lee;Etri Kocaqi;
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文献类型：
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作者：
Abdalla Ahmed;Jibran Nehal Syed;Lijun Chi;Yaxu Wang;C. Perez-Romero;Dorothy Lee;Etri Kocaqi;
心力衰竭时心脏代谢紊乱，但其潜在机制尚不清楚。在这里，我们发现赖氨酸脱甲基酶8（Kdm 8）通过抑制Tbx15来维持一个活跃的线粒体基因网络，从而防止扩张型心肌病导致致命的心力衰竭。在扩张型心肌病发生之前，小鼠心肌细胞中Kdm 8的缺失增加了H3K36 me2，并激活了Tbx15和抑制了NAD+通路中的靶基因。补充NAD+可预防Kdm 8突变小鼠的扩张型心肌病，TBX15过表达可减弱NAD+激活的心肌细胞呼吸。此外，KDM8在受扩张型心肌病影响的人类心脏中下调，较高的TBX15表达定义了受影响心脏的一个亚组，其编码线粒体蛋白的基因下调最强。因此，KDM8抑制TBX15以维持心脏代谢。我们的研究结果表明，代谢基因网络的表观遗传失调启动心肌恶化心力衰竭，并可能成为扩张型心肌病异质性的基础。
Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Here, we show that lysine demethylase 8 (Kdm8) maintains an active mitochondrial gene network by repressingTbx15, thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion ofKdm8in mouse cardiomyocytes increased H3K36me2 with activation ofTbx15and repression of target genes in the NAD+pathway before dilated cardiomyopathy initiated. NAD+supplementation prevented dilated cardiomyopathy inKdm8mutant mice, andTBX15overexpression blunted NAD+-activated cardiomyocyte respiration. Furthermore,KDM8was downregulated in human hearts affected by dilated cardiomyopathy, and higherTBX15expression defines a subgroup of affected hearts with the strongest downregulation of genes encoding mitochondrial proteins. Thus, KDM8 repressesTBX15to maintain cardiac metabolism. Our results suggest that epigenetic dysregulation of metabolic gene networks initiates myocardium deterioration toward heart failure and could underlie heterogeneity of dilated cardiomyopathy.