H3K9 trimethylation in active compartments optimizes stimulus-regulated transcription by restricting usage of CTCF sites in SINE-B2 repeats [ChIP-Seq]

ABSTRACT: Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification involved in the formation of constitutive heterochromatin, gene repression and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin compartments to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the role of SETDB1 in stimulus-inducible gene expression in macrophages, we unexpectedly found that upon SETDB1 depletion, loss of H3K9me3 in active compartments was associated with increased recruitment of CTCF to >1,600 DNA-binding motifs contained within SINE-B2 repeats, a previously unidentified target of SETDB1-mediated repression. CTCF is an essential regulator of chromatin folding that restrains DNA looping by cohesin, thus creating boundaries among adjacent topological domains. Increased CTCF binding to SINE-B2 repeats generated novel boundaries within topological domains containing lipopolysaccharide-inducible genes, correlating with their impaired regulation in response to stimulation. These data indicate a role of H3K9me3 in restraining genomic distribution and activity of CTCF, with impact on chromatin organization and gene regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE189971 | GEO | 2022/03/31

REPOSITORIES: GEO