SETD1B controls cognitive function via cell type specific regulation of neuronal identity genes

Abstract

Histone-3-lysine-4-methylation (H3K4me) is mediated by six different lysine methyltransferases (KMTs). Amongst these enzymes SET domain containing 1b (SETD1B) has been linked to intellectual disability but its role in the adult brain has not been studied yet. Here we show that mice lacking Setd1b from excitatory neurons of the adult forebrain exhibit severe memory impairment. By combining neuron-specific ChIP-seq, RNA-seq and single cell RNA-seq approaches we show that Setd1b controls the expression of neuronal-identity genes with a broad H3K4me3 peak linked to learning and memory processes. Our data furthermore suggest that basal neuronal gene-expression is ensured by other H3K4 KMTs such as Kmt2a and Kmt2b while the additional presence of Setd1b at the single cell level provides transcriptional consistency to the expression of genes important for learning & memory.

The role of histone methyltransferases in neurocognitive disorders associated with brain size abnormalities

“…In mice, deletion of Setd1b at early embryonic stages did not appear to be required for neural stem cell (NSC) survival or proliferation (Bledau et al, 2014). However, postnatal deletion of Setd1b in excitatory forebrain cortical neurons led to severe learning impairment and altered the expression of neural genes involved in learning and memory (Michurina et al, 2022). Therefore, SETD1B appears to control primarily neuronal function.…”