Mina53 demethylates histone H4 arginine 3 asymmetric dimethylation to regulate neural stem/progenitor cell identity

• Published in: Nature communications 2024-11, Vol.15 (1), p.10227-14, Article 10227
• Main Authors: Zhou, Lixiao, Zhao, Xingsen, Sun, Jie, Zou, Kun, Huang, Xiaoli, Yu, Liyang, Wu, Mingxuan, Wang, Yong, Li, Xuekun, Yi, Wen
• Format: Article
• Language: English
• Subjects: 13/106; 13/89; 14/1; 14/19; 38/77; 38/91; 631/337/176; 631/45/607/1172; 631/92/458/1648; Animals; Arginine; Arginine - metabolism; Asymmetry; Cell Differentiation; Cell growth; Cell Proliferation; Cells (biology); Clonal deletion; Cognitive ability; Demethylation; DNA methylation; Epigenetics; Gene expression; Gene regulation; Genes; HEK293 Cells; Histone H4; Histones; Histones - metabolism; Humanities and Social Sciences; Humans; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Male; Methylation; Mice; Mice, Transgenic; Molecular dynamics; Molecular Dynamics Simulation; Monomethyl-L-arginine; multidisciplinary; Myc protein; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Progenitor cells; Science; Science (multidisciplinary); Transgenic mice
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54680-6

Arginine methylation of histones plays a critical role in regulating gene expression. The writers (methyltransferases) and readers of methylarginine marks are well-known, but the erasers–arginine demethylases–remain mysterious. Here we identify Myc-induced nuclear antigen 53 (Mina53), a jumonji C domain containing protein, as an arginine demethylase for removing asymmetric di-methylation at arginine 3 of histone H4 (H4R3me2a). Using a photoaffinity capture method, we first identify Mina53 as an interactor of H4R3me2a. Biochemical assays in vitro and in cells characterize the arginine demethylation activity of Mina53. Molecular dynamics simulations provide further atomic-level evidence that Mina53 acts on H4R3me2a. In a transgenic mouse model, specific Mina53 deletion in neural stem/progenitor cells prevents H4R3me2a demethylation at distinct genes clusters, dysregulating genes important for neural stem/progenitor cell proliferation and differentiation, and consequently impairing the cognitive function of mice. Collectively, we identify Mina53 as a bona fide H4R3me2a eraser, expanding the understanding of epigenetic gene regulation. Mina53 is identified as the enzyme responsible for removing histone 4 arginine 3 asymmetric dimethylation and is important to regulate gene expressions critical for neural stem/progenitor cell proliferation.