Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice

Epigenetic regulation of gene expression through histone modifications like methylation of various lysine residues are essential for embryonic development. Here we removed SETD2, a methyltransferase for histone 3 lysine 36 trimethylation (H3K36me3), in the developing dorsal forebrain in mice and show it is required for proper area patterning (arealization) of the neocortex and the formation of thalamo-cortico-thalamic circuits by maintaining the expression of clustered protocadherin (Pcdh) genes in an H3K36me3 methyltransferase-dependent manner. Moreover, the Setd2 mutant mice exhibit defects in social interaction, motor endurance and spatial memory, reminiscent of patients with the Sotos-like syndrome bearing SETD2 mutations. Overall design: Cortex mRNA profiles of E13.5 control and Emx1-Cre;Setd2 fl/fl mice were generated by deep sequencing, in triplicate, using Illumina NovaSeq 6000.