Cellular metabolism is linked to epigenetics, but the biophysical effects of metabolism on chromatin structure and implications for gene regulation remain largely unknown. Here, using a broken tricarboxylic acid (TCA) cycle and disrupted electron transport chain (ETC) exemplified by succinate dehydrogenase subunit C (SDHC) deficiency, we investigated the effects of metabolism on chromatin architecture over multiple distance scales [nucleosomes (~10^2 bp), topologically-associated domains (TADs; ~10^5 - 10^6 bp), and chromatin compartments (10^6 - 10^8 bp)]. Metabolically-driven hyperacylation of histones led to weakened nucleosome positioning in multiple types of chromatin, and we further demonstrate that lysine acylation directly destabilizes histone octamer-DNA interactions. Hyperacylation of cohesin subunits correlated with decreased mobility on interphase chromatin and increased TAD boundary strength, suggesting that cohesin is metabolically regulated. Erosion of chromatin compartment distinctions reveals metabolic regulation of chromatin liquid-liquid phase separation. The TCA cycle and ETC thus modulate chromatin structure over multiple distance scales.

中文翻译：

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蛋白质过度酰化将线粒体功能障碍与核组织联系起来

细胞代谢与表观遗传学有关，但是代谢对染色质结构的生物物理影响及其对基因调控的影响仍然未知。在这里，我们使用断裂的三羧酸（TCA）循环和破坏的电子传输链（ETC）（例如琥珀酸脱氢酶亚基C（SDHC）缺乏症），研究了代谢对染色质结构在多个距离尺度上的影响[核小体（〜10 ^ 2 bp），拓扑相关的域（TAD;〜10 ^ 5-10 ^ 6 bp）和染色质区室（10 ^ 6-10 ^ 8 bp）]。组蛋白的代谢驱动超酰化作用导致多种类型的染色质中核小体定位减弱，并且我们进一步证明赖氨酸酰化作用直接破坏了组蛋白八聚体-DNA相互作用的稳定性。粘附素亚基的过度酰化与相间染色质的迁移率降低和TAD边界强度增加相关，表明粘附素受代谢调节。染色质区室区别的侵蚀揭示了染色质液-液相分离的代谢调控。因此，TCA循环和ETC可以在多个距离范围内调节染色质结构。