The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus

• Published in: Nature communications Vol. 12; no. 1; p. 256
• Main Authors: Huisman, Christian, Kim, Young A, Jeon, Shin, Shin, Bongjin, Choi, Jeonghoon, Lim, Su Jeong, Youn, Sung Min, Park, Younjung, K C, Medha, Kim, Sangsoo, Lee, Soo-Kyung, Lee, Seunghee, Lee, Jae W
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 11.01.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animal models; Animals; Base Sequence; Congenital defects; Dwarfism; Dwarfism - metabolism; Embryo, Mammalian - metabolism; Epigenesis, Genetic; Epigenetics; Etiology; Gene expression; Gene Expression Regulation, Developmental; Growth hormone; Growth hormone-releasing hormone; Growth Hormone-Releasing Hormone - biosynthesis; Growth hormones; HEK293 Cells; Histone deacetylase; Histone H3; Histone methyltransferase; Histone-Lysine N-Methyltransferase - metabolism; Histones; Humans; Hypothalamus; Hypothalamus - cytology; Hypothalamus - embryology; Lysine; Male; Methyltransferase; Mice; Mice, Knockout; Models, Biological; Molecular modelling; Mutants; Mutation; Neurons; Neurons - metabolism; Nuclear Respiratory Factor 1 - metabolism; Phenotypes; Phenylbutyrates - pharmacology; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20511-7

In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltransferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 regulates the development of growth hormone-releasing hormone (GHRH)-producing neurons in the mouse hypothalamus. Our two Mll4 mutant mouse models exhibit dwarfism phenotype and impairment of the developmental programs for GHRH-neurons. Our ChIP-seq analysis reveals that, in the developing mouse hypothalamus, Mll4 interacts with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production in Mll4 mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRH-neurons and dwarfism phenotype in mice.