Creative Research Initiatives Center for Epigenetic Code and Diseases, Department of Biological Sciences, Seoul National University, Seoul, 08826, South Korea.
Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, 94720, USA.
Nat Commun. 2020 Dec 8;11(1):6297. doi: 10.1038/s41467-020-20080-9.
Autophagy is a catabolic process through which cytoplasmic components are degraded and recycled in response to various stresses including starvation. Recently, transcriptional and epigenetic regulations of autophagy have emerged as essential mechanisms for maintaining homeostasis. Here, we identify that coactivator-associated arginine methyltransferase 1 (CARM1) methylates Pontin chromatin-remodeling factor under glucose starvation, and methylated Pontin binds Forkhead Box O 3a (FOXO3a). Genome-wide analyses and biochemical studies reveal that methylated Pontin functions as a platform for recruiting Tip60 histone acetyltransferase with increased H4 acetylation and subsequent activation of autophagy genes regulated by FOXO3a. Surprisingly, CARM1-Pontin-FOXO3a signaling axis can work in the distal regions and activate autophagy genes through enhancer activation. Together, our findings provide a signaling axis of CARM1-Pontin-FOXO3a and further expand the role of CARM1 in nuclear regulation of autophagy.
自噬是一种分解代谢过程，细胞质成分在受到饥饿等各种应激时会被降解和回收。最近，自噬的转录和表观遗传调控已成为维持体内平衡的重要机制。在这里，我们发现共激活因子相关精氨酸甲基转移酶 1（CARM1）在葡萄糖饥饿下甲基化 Pontin 染色质重塑因子，甲基化的 Pontin 与 Forkhead Box O 3a（FOXO3a）结合。全基因组分析和生化研究表明，甲基化的 Pontin 作为一种平台，可招募 Tip60 组蛋白乙酰转移酶，增加 H4 乙酰化，随后激活 FOXO3a 调控的自噬基因。令人惊讶的是，CARM1-Pontin-FOXO3a 信号轴可以在远端区域发挥作用，并通过增强子激活来激活自噬基因。总之，我们的研究结果提供了 CARM1-Pontin-FOXO3a 的信号轴，并进一步扩展了 CARM1 在自噬的核调节中的作用。
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