Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α.
Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α.
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DOI：
10.1016/j.celrep.2015.12.043
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发表时间：
2016-01-26
期刊：
影响因子：
8.8
通讯作者：
Walsh MJ
中科院分区：
文献类型：
--
作者：
Aguilo F;Li S;Balasubramaniyan N;Sancho A;Benko S;Zhang F;Vashisht A;Rengasamy M;Andino B;Chen CH;Zhou F;Qian C;Zhou MM;Wohlschlegel JA;Zhang W;Suchy FJ;Walsh MJ
过氧化物酶体增殖体激活受体- γ辅激活因子1α (PGC-1α)是一种转录辅激活因子，在适应性代谢反应中起核心作用。PGC-1α在残基K779处分别被甲基转移酶SET7/9和赖氨酸特异性去甲基酶1A （LSD1）动态甲基化和非甲基化。甲基化的PGC-1α[K779me]与spt - ada - gcn5 -乙酰转移酶（SAGA）复合物、中介成员MED1和MED17以及NOP2/Sun RNA甲基转移酶7 （NSUN7）的相互作用增强转录，并伴随增强子RNA （eRNAs）上的m5C标记。与此一致的是，肝细胞模型系统中Set7/9和NSun7的缺失导致PGC-1α靶基因Pfkl、Sirt5、Idh3b和Hmox2的缺失，同时伴随着与这些位点相关的erna水平的降低。eRNA物种中m5C的富集与体内空腹代谢应激一致。总的来说，这些发现说明了PGC-1α在eRNA水平上施加复杂的表观遗传回路来微调能量代谢。
The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m5C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b and Hmox2, which was accompanied with a decrease in the eRNAs levels associated to these loci. Enrichment of m5C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.