Genome-wide maps of gene transcription and chromatin state in mouse Setdb1 wildtype and CK-cre conditional knockout brain.. Mus musculus

We report locus-specific disintegration of megabase-scale chromosomal conformations after Kmt1e/Setdb1 histone H3-lysine 9 methyltransferase ablation in mouse brian. Histone modification, CCCTC-binding factor (CTCF), transcriptome and ‘3D genome’ (in situ Hi-C) mappings each identified a uniquely affected ~1Mb domain on chromosome 18 in cortical and striatal neurons, encompassing the Protocadherin cell adhesion gene clusters (cPcdh). Setdb1-deficient neuronal genomes showed de novo CTCF occupancies at thousands of cryptic binding sites and locus-specific disintegration of 1Mb cPcdh higher order chromatin. Loss of long-range repressive chromosomal conformations triggered massively increased proportions of neurons expressing specific cPcdh genes due to relaxation of stochastic constraint. Setdb1, shielding mature neuronal genomes from excess CTCF binding, maintains TAD integrity essential for mouse brain function. Overall design: RNAseq, histone H3K9me3 ChIPseq, H3K27ac ChIPseq, CTCF ChIPseq, and in situ HiC on anti-NeuN+ neuronal nuclei from adult Setdb1 WT and KO cortex