Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation
Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation
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DOI：
10.1038/s44161-023-00365-0
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发表时间：
2023-12-01
期刊：
影响因子：
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通讯作者：
Swietach，Pawel
中科院分区：
文献类型：
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作者：
Park，Kyung Chan;Crump，Nicholas T.;Swietach，Pawel
促丙底物和肠道细菌产生丙酸，一种翻译后蛋白修饰剂。在这项研究中，我们使用丙酸血症（PA）小鼠模型来研究丙酸代谢紊乱如何导致组蛋白修饰和基因表达改变，从而影响心功能。在PA小鼠中培养血浆丙酸替代物，但雌性心脏在酰基辅酶a、组蛋白丙酰化和乙酰化以及转录方面表现出更深刻的变化。这些导致中度舒张功能障碍，舒张Ca2+升高，收缩末期心室容积扩大，卒中容积减少。丙酸被追溯到组蛋白H3丙酸化，并引起全基因组乙酰化增加，包括pde9aandmme的启动子，这些基因通过缩小cGMP信号传导与收缩功能障碍相关。男性心脏中较不严重的表型与β-丙氨酸积累有关。用丙酸处理培养的肌细胞，提高β-丙氨酸可降低丙酰辅酶a水平，表明其机制关系。因此，我们将丙酸代谢紊乱与影响心功能的表观遗传变化联系起来。
Propiogenic substrates and gut bacteria produce propionate, a post-translational protein modifier. In this study, we used a mouse model of propionic acidaemia (PA) to study how disturbances to propionate metabolism result in histone modifications and changes to gene expression that affect cardiac function. Plasma propionate surrogates were raised in PA mice, but female hearts manifested more profound changes in acyl-CoAs, histone propionylation and acetylation, and transcription. These resulted in moderate diastolic dysfunction with raised diastolic Ca2+, expanded end-systolic ventricular volume and reduced stroke volume. Propionate was traced to histone H3 propionylation and caused increased acetylation genome-wide, including at promoters ofPde9aandMme, genes related to contractile dysfunction through downscaled cGMP signaling. The less severe phenotype in male hearts correlated with β-alanine buildup. Raising β-alanine in cultured myocytes treated with propionate reduced propionyl-CoA levels, indicating a mechanistic relationship. Thus, we linked perturbed propionate metabolism to epigenetic changes that impact cardiac function.