组蛋白去乙酰化酶HDAC8的表达升高会抑制坏死性小肠结肠炎中的精氨酸-脯氨酸代谢。
Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis.
作者信息
Guo Ting, Hu Shaohua, Xu Weijue, Zhou Jin, Chen Feng, Gao Tingting, Qu Wenqian, Chen Faling, Lv Zhibao, Lu Li
机构信息
Department of General Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China.
Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China.
出版信息
iScience. 2023 May 14;26(6):106882. doi: 10.1016/j.isci.2023.106882. eCollection 2023 Jun 16.
Epigenetic alterations are especially important in necrotizing enterocolitis (NEC). Here, we reported that histone deacetylase 8 (HDAC8) plays a previously unknown role in modulating arginine metabolism via acetylation of histone 3 lysine 9 (acetyl-H3K9) regulation during the pathogenesis of NEC. We found that HDAC8 was upregulated in humans and mice intestinal samples with NEC, while selective inhibition of HDAC8 expression ameliorated NEC. HDAC8 regulates enzymes involved in the metabolic conversion of proline to arginine (PRODH, PRODH2, OAT, and OTC) and arginine to ornithine (ARG1). The results showed that H3K9ac signal in the PRODH/PRODH2 promoter region was mediated by HDAC8. Additionally, the decreased concentration of butyric acid was strongly correlated with elevated HDAC8 levels and circulating arginine, which may result from an unbalanced Firmicutes/Bacteroidetes ratio. These results reveal previously underappreciated roles of microbial metabolites and HDAC8 to coordinate the arginine metabolism during NEC development.
表观遗传改变在坏死性小肠结肠炎（NEC）中尤为重要。在此，我们报道组蛋白去乙酰化酶8（HDAC8）在NEC发病机制中通过调节组蛋白3赖氨酸9（乙酰化-H3K9）的乙酰化作用，在调节精氨酸代谢方面发挥了前所未知的作用。我们发现HDAC8在患有NEC的人类和小鼠肠道样本中上调，而选择性抑制HDAC8表达可改善NEC。HDAC8调节参与脯氨酸向精氨酸代谢转化（脯氨酸脱氢酶、脯氨酸脱氢酶2、鸟氨酸转氨酶和鸟氨酸转氨甲酰酶）以及精氨酸向鸟氨酸转化（精氨酸酶1）的酶。结果表明，脯氨酸脱氢酶/脯氨酸脱氢酶2启动子区域的H3K9ac信号由HDAC8介导。此外，丁酸浓度降低与HDAC8水平升高和循环精氨酸密切相关，这可能是由于厚壁菌门/拟杆菌门比例失衡所致。这些结果揭示了微生物代谢产物和HDAC8在NEC发展过程中协调精氨酸代谢方面此前未被充分认识的作用。
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