Postnatal expression of the lysine methyltransferase SETD1B is essential for learning and the regulation of neuron‐enriched genes

• DOI: 10.15252/embj.2020106459
• Publication Date: 2021-11-22T12:48:39Z
• Authors: Alexandra Michurina; M Sadman Sakib; Cemil Kerimoglu; Dennis Manfred Kr...; Lalit Kaurani; Md Rezaul Islam; Parth Devesh Joshi; Sophie Schröder; Tonatiuh Pena Cen...; Jiayin Zhou; Ranjit Pradhan; Julia Cha; Xingbo Xu; Gregor Eichele; Elisabeth M Zeisberg; Andrea Kranz; A Francis Stewart; André Fischer
• Keywords: 0301 basic medicine; metabolism [Myeloid-Lymphoid Leukemia Protein]; Kmt2b protein, mouse; metabolism [Histones]; genetics [Transcriptome]; metabolism [Hippocampus]; Cre recombinase; Hippocampus; deficiency [Histone-Lysine N-Methyltransferase]; cognitive diseases; Epigenesis, Genetic; Histones; Mice; 03 medical and health sciences; metabolism [Integrases]; Memory; ddc:570; Animals; Learning; physiology [Learning]; metabolism [Cell Nucleus]; physiology [Memory]; Cell Nucleus; Mice, Knockout; Neurons; Integrases; metabolism [Calcium-Calmodulin-Dependent Protein Kinase Type 2]; Articles; Histone-Lysine N-Methyltransferase; ChIP-seq; Mice, Inbred C57BL; Animals, Newborn; Gene Expression Regulation; metabolism [Neurons]; histone-methylation; Kmt2a protein, mouse; metabolism [Histone-Lysine N-Methyltransferase]; genetics [Histone-Lysine N-Methyltransferase]; learning and memory; Transcription Initiation Site; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Transcriptome; histone H3 trimethyl Lys4; Myeloid-Lymphoid Leukemia Protein

In mammals, histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Among these enzymes, SETD1B (SET domain containing 1b) has been linked to syndromic intellectual disability in human subjects, but its role in the mammalian postnatal brain has not been studied yet. Here, we employ mice deficient for Setd1b in excitatory neurons of the postnatal forebrain, and combine neuron-specific ChIP-seq and RNA-seq approaches to elucidate its role in neuronal gene expression. We observe that Setd1b controls the expression of a set of genes with a broad H3K4me3 peak at their promoters, enriched for neuron-specific genes linked to learning and memory function. Comparative analyses in mice with conditional deletion of Kmt2a and Kmt2b histone methyltransferases show that SETD1B plays a more pronounced and potent role in regulating such genes. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B-dependent regulation of H3K4me levels in postnatal neurons is critical for cognitive function.