biostudies-literatureLiu XAmerican Cancer SocietyNCATS NIH HHSU.S. Department of Health & Human Services | NIH | National Cancer InstituteU.S. Department of DefenseNCI NIH HHSU.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer InstituteNIGMS NIH HHSCancer Prevention and Research Institute of Texas1721-1735https://www.ebi.ac.uk/biostudies/studies/S-EPMC9674084biostudies-literatureUnknown54(11)Histone post-translational modifications (PTMs) are important for regulating various DNA-templated processes. Here, we report the existence of a histone PTM in mammalian cells, namely histone H3 with hydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by the proline hydroxylase EGLN2. We show that H3P16oh enhances direct binding of KDM5A to its substrate, histone H3 with trimethylation at the fourth lysine residue (H3K4me3), resulting in enhanced chromatin recruitment of KDM5A and a corresponding decrease of H3K4me3 at target genes. Genome- and transcriptome-wide analyses show that the EGLN2-KDM5A axis regulates target gene expression in mammalian cells. Specifically, our data demonstrate repression of the WNT pathway negative regulator DKK1 through the EGLN2-H3P16oh-KDM5ANature geneticsHistone H3 proline 16 hydroxylation regulates mammalian gene expression.PMC9674084R01 CA215284R01CA2152841R35CA197684RSG-18-059-01-TBER01CA211336R01CA211732R01 CA211336UL1 TR001863R01 CA211732R01CA256833DoD W81XWH1910813R01 CA2568331R35GM126900R35 GM126900R35 CA197684RR190058Boyer JAStrahl BDGuo YWu QRodriguez JTsai YHUryu HLiao CWang JShi XZhang QGong WLiu XZhao SChen XBaldwin ASZhang CZhou JYan QXie LJain KLi Mvon Kriegsheim ALuo WHu LWang GGfalseHistone H3 proline 16 hydroxylation regulates mammalian gene expression.Histone post-translational modifications (PTMs) are important for regulating various DNA-templated processes. Here, we report the existence of a histone PTM in mammalian cells, namely histone H3 with hydroxylation of proline at residue 16 (H3P16oh), which is catalyzed by the proline hydroxylase EGLN2. We show that H3P16oh enhances direct binding of KDM5A to its substrate, histone H3 with trimethylation at the fourth lysine residue (H3K4me3), resulting in enhanced chromatin recruitment of KDM5A and a corresponding decrease of H3K4me3 at target genes. Genome- and transcriptome-wide analyses show that the EGLN2-KDM5A axis regulates target gene expression in mammalian cells. Specifically, our data demonstrate repression of the WNT pathway negative regulator DKK1 through the EGLN2-H3P16oh-KDM5A2022-01-01T00:00:00Z2022 Nov2025-04-19T17:18:41.194Z2025-02-19T03:25:55.338ZS-EPMC96740843634794410.1038/s41588-022-01212-x