Histone methyltransferase G9a protects against acute liver injury through GSTP1
Histone methyltransferase G9a protects against acute liver injury through GSTP1
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组蛋白甲基转移酶 G9a 通过 GSTP1 预防急性肝损伤
DOI：
10.1038/s41418-019-0412-8
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发表时间：
2020-04-01
影响因子：
12.4
通讯作者：
Zheng, Ling
中科院分区：
文献类型：
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作者：
Zhang, Yu;Xue, Weili;Zheng, Ling
急性肝损伤通常由细菌内毒素/脂多糖（LPS）和药物过量（如对乙酰氨基酚（APAP））引起。表观遗传修饰在急性肝损伤中的确切作用仍然难以捉摸。在这里，我们研究了组蛋白甲基转移酶G9 a在LPS或APAP过量诱导的急性肝损伤中的作用。在半乳糖胺致敏下，肝脏特异性G9 a缺陷小鼠（L-G9 a −/−）在LPS注射后显示出100%的死亡率，而对照组和L-G9 a +/−同窝小鼠显示出非常轻微的死亡率。此外，废除肝脏G9 a或抑制G9 a的甲基转移酶活性加重LPS诱导的肝损伤。同样，在亚致死APAP过量的情况下，L-G9 a −/−小鼠表现出更严重的肝损伤。从机制上讲，G9 a的消融抑制了Gstp 1/2（两种肝脏解毒酶）启动子处的H3 K9 me 1水平，从而抑制了它们的转录。值得注意的是，用重组小鼠GSTP 1治疗L-G9 a −/−小鼠逆转了LPS或APAP过量诱导的肝损伤。总之，我们确定了G9 a-GSTP 1轴在保护急性肝损伤中的新的有益作用。
Acute liver injury is commonly caused by bacterial endotoxin/lipopolysaccharide (LPS), and by drug overdose such as acetaminophen (APAP). The exact role of epigenetic modification in acute liver injury remains elusive. Here, we investigated the role of histone methyltransferase G9a in LPS- or APAP overdose-induced acute liver injury. Underd-galactosamine sensitization, liver-specific G9a-deficient mice (L-G9a−/−) exhibited 100% mortality after LPS injection, while the control and L-G9a+/−littermates showed very mild mortality. Moreover, abrogation of hepatic G9a or inhibiting the methyltransferase activity of G9a aggravated LPS-induced liver damage. Similarly, under sublethal APAP overdose, L-G9a−/−mice displayed more severe liver injury. Mechanistically, ablation of G9a inhibited H3K9me1 levels at the promoters ofGstp1/2, two liver detoxifying enzymes, and consequently suppressed their transcription. Notably, treating L-G9a−/−mice with recombinant mouse GSTP1 reversed the LPS- or APAP overdose-induced liver damage. Taken together, we identify a novel beneficial role of G9a-GSTP1 axis in protecting against acute liver injury.