Epigenetic Regulation of Autophagy by the Methyltransferase G9a
Epigenetic Regulation of Autophagy by the Methyltransferase G9a
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DOI：
10.1128/mcb.00813-13
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发表时间：
2013-10-01
影响因子：
5.3
通讯作者：
Billadeau, Daniel D.
中科院分区：
文献类型：
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作者：
de Narvajas, Amaia Artal-Martinez;Gomez, Timothy S.;Billadeau, Daniel D.
巨噬是一种进化上保守的细胞过程，涉及蛋白质和细胞器的清除。尽管在饥饿、缺氧或受体刺激过程中协调自噬诱导的细胞质机制已被广泛研究，但启动和维持自噬过程的关键表观遗传事件仍不清楚。在这里，我们表明甲基转移酶G9a通过重塑染色质景观来协调自噬体形成的关键调节因子的转录激活。药物抑制或RNA干扰（RNAi）介导的G9a抑制诱导LC3B表达和脂化，脂化依赖于G9a的RNA合成、蛋白质翻译和甲基转移酶活性。在正常情况下，G9a与LC3B、WIPI1和DOR基因启动子结合，在表观遗传学上抑制它们。然而，G9a和G9a抑制组蛋白标记在饥饿和受体刺激的幼稚T细胞激活过程中被去除，这是两种巨噬的生理诱导剂。此外，我们发现c-Jun n -末端激酶（JNK）途径参与了幼稚t细胞活化过程中自噬基因表达的调控。综上所述，这些发现表明G9a直接抑制已知参与自噬过程的基因，抑制G9a介导的表观遗传抑制是自噬过程中重要的调控机制。
Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, the key epigenetic events that initiate and maintain the autophagy process remain unknown. Here we show that the methyltransferase G9a coordinates the transcriptional activation of key regulators of autophagosome formation by remodeling the chromatin landscape. Pharmacological inhibition or RNA interference (RNAi)-mediated suppression of G9a induces LC3B expression and lipidation that is dependent on RNA synthesis, protein translation, and the methyltransferase activity of G9a. Under normal conditions, G9a associates with the LC3B, WIPI1, and DOR gene promoters, epigenetically repressing them. However, G9a and G9a-repressive histone marks are removed during starvation and receptor-stimulated activation of naive T cells, two physiological inducers of macroautophagy. Moreover, we show that the c-Jun N-terminal kinase (JNK) pathway is involved in the regulation of autophagy gene expression during naive-T-cell activation. Together, these findings reveal that G9a directly represses genes known to participate in the autophagic process and that inhibition of G9a-mediated epigenetic repression represents an important regulatory mechanism during autophagy.