Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis.
Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis.
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DOI：
10.1016/j.isci.2023.106882
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发表时间：
2023-06-16
期刊：
影响因子：
5.8
通讯作者：
Lu, Li
中科院分区：
文献类型：
--
作者：
Guo, Ting;Hu, Shaohua;Xu, Weijue;Zhou, Jin;Chen, Feng;Gao, Tingting;Qu, Wenqian;Chen, Faling;Lv, Zhibao;Lu, Li
表观遗传学改变在坏死性小肠结肠炎(NEC)中尤为重要。在此，我们报道了组蛋白脱乙酰酶8(HDAC8)在NEC发病过程中通过组蛋白3赖氨酸9(乙酰基-H3K9)的乙酰化调节精氨酸代谢的未知作用。我们发现，NEC可上调人和小鼠肠道组织中HDAC8的表达，而选择性抑制HDAC8的表达可改善NEC。HDAC8调节与精氨酸(PRODH、PRODH2、OAT和OTC)和精氨酸(ARG1)代谢转化相关的酶。结果表明，Prodh/PRODH2启动子区域的H3K9ac信号由HDAC8介导。此外，丁酸浓度的降低与HDAC8水平的升高和循环精氨酸的升高密切相关，这可能是由于Firmicents/类杆菌比例失衡所致。这些结果揭示了以前被低估的微生物代谢物和HDAC8在NEC发育过程中协调精氨酸代谢的作用。HDAC8在NEC中上调，抑制HDAC8可促进NEC发育过程中HDAC8调节精氨酸-脯氨酸代谢途径H3K9Ac是HDAC8的底物，调节精氨酸转化酶丁酸抑制HDAC8表达并影响NEC精氨酸浓度在生物科学；遗传学；分子生物学；分子遗传学
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. HDAC8 was upregulated in NEC and suppressing HDAC8 could improve NEC HDAC8 regulated the arginine-proline metabolism pathway during NEC development H3K9ac was a substrate of HDAC8 to regulate the enzymes for arginine conversion Butyrate inhibited HDAC8 expression and affected arginine concentration in NEC Biological sciences; Genetics; Molecular biology; Molecular Genetics
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