Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis

Ting Guo; Shaohua Hu; Weijue Xu; Jin Zhou; Feng Chen; Tingting Gao; Wenqian Qu; Faling Chen; Zhibao Lv; Li Lu

doi:10.1016/j.isci.2023.106882

Elevated expression of histone deacetylase HDAC8 suppresses arginine-proline metabolism in necrotizing enterocolitis

iScience. 2023 May 14;26(6):106882. doi: 10.1016/j.isci.2023.106882. eCollection 2023 Jun 16.

Authors

Ting Guo¹, Shaohua Hu², Weijue Xu¹, Jin Zhou¹, Feng Chen¹, Tingting Gao¹, Wenqian Qu¹, Faling Chen¹, Zhibao Lv¹, Li Lu¹

Affiliations

¹ Department of General Surgery, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China.
² Department of Clinical Laboratory, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200040, China.

Abstract

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.

Keywords: Biological sciences; Genetics; Molecular Genetics; Molecular biology.