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

Abstract

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 RNAseq 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.

Conserved reduction of m6A marks during aging and neurodegeneration is linked to altered translation of synaptic transcripts

“…Cell type specific chromatin isolation and ChIP sequencing was performed as previously described 92 93 . 3-4 CA1 were pooled for each replicate and nuclei were FACS sorted by NeuN expression.…”

Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies

“…Frontiers in Cell and Developmental Biology frontiersin.org (Jones et al, 2012;Reynisdottir et al, 2022); (Sheppard and Quintero-Rivera, 1993) Conditional deletions in mice: cognitive and behavioral alterations (spatial working memory, nest building, anxiety); reduction of H3K4me3 at promoters of genes associated with neuropsychiatric susceptibility in cortical neurons; reduced H3K4me1 at enhancers (Jakovcevski et al, 2015;Kerimoglu et al, 2017;Michurina et al, 2022) KO mouse embryonic fibroblasts: reduction of H3K4me2/3 and reduced expression of HoxA9 (Gregory et al, 2007) KMT2B/MLL2/ WBP7…”

“…H3K4me1/2/3 KMT2B-related dystonia (DYT18) (de novo or inherited/autosomal dominant/) (Zech et al, 2016;Meyer et al, 2017) KMT2B non-dystonia neurodevelopmental phenotype (Cif et al, 2020) Conditional KO in mouse excitatory forebrain neurons: hippocampus-dependent learning impairment (short and long-term memory), reduction of H3K4me1 (Kerimoglu et al, 2013;Kerimoglu et al, 2017;Michurina et al, 2022) Patient-derived fibroblasts: endo-lysosomal processing abnormalities (cholesterol and sphingolipid accumulation) (Zhao et al, 2018) KMT2C/MLL3/ HALR H3K4me1 (Cho et al, 2007;Hu et al, 2013) Kleefstra Syndrome 2 (de novo/autosomal dominant) (Koemans et al, 2017;Siano et al, 2022) Double KO of mouse embryonic stem cell, kmt2c KO and conditional kmt2d KO: reduction of H3K4me1/2 (Wang et al, 2016) KMT2D/MLL4 (MLL2)/ALR H3K4me1 (Hu et al, 2013)/2/3 Kabuki Syndrome (de novo or inherited//autosomal dominant/1/32,000) (Kuroki et al, 1981;Ng et al, 2010); (Adam et al, 1993) Conditional KO mice and immortalized BAT: diminution of muscle mass and BAT, dysregulation of genes involved in adipocytes and myocytes differentiation, reduction of H3K4me1/2 at enhancers (Lee et al, 2013) Double KO mouse embryonic fibroblasts, kmt2c KO and conditional kmt2d KO: reduction of H3K4me1/2 (Wang et al, 2016) KO in Human B-cell culture (Gm12878 cells) by siRNA: downregulation of the ITGB7 transcript. Kmt2d+/bGeo mouse: immunodeficiency (decrease of IgA and Peyer patches) (Pilarowski et al, 2020) KMT2F/SETD1A/ SET1A…”

“…H3K4me3 IDDSELD (de novo/autosomal dominant) (Labonne et al, 2016;Hiraide et al, 2019;Michurina et al, 2022) Post-natal conditional deletions in murine forebrain excitatory neurons: hippocampusdependent learning impairment, diminution of H3K4me3 near transcription start site (TSS) of genes implicated in neuronal plasticity (Michurina et al, 2022) KMT2H/ASH1L H3K4, (Gregory et al, 2007) H3K36me1/2 (Tanaka et al, 2007;Miyazaki et al, 2013) ID, ASD, seizures (de novo or inherited/autosomal dominant)/ (De Rubeis et al, 2014;Stessman et al, 2017) Neuronal KO using inducible RNAi in Drosophila model: ASD and ID behavioral assay with impairment of higher cognitive functions (Stessman et al, 2017) KD in HEK-293 T with shASH1L (Gregory et al, 2007): reduction of H3K4me3 with reduce expression of Hox genes (Continued on following page)…”

“…However, RNA sequencing and Chromatin Immunoprecipitation Sequencing (ChIP-seq) analysis have shown limited overlap of the gene expression profiles between KMT2A and KMT2B-KO mice (Michurina et al, 2022). Moreover, these studies have highlighted that the observed reduction of H3K4me3 at specific promoters was dependent on the specific KMT2-KO (Kerimoglu et al, 2013;Kerimoglu et al, 2017).…”