New publication in "Nature Communications"

New publication in "Nature Communications"

SETDB1 is a histone methyltransferase that generates H3K9me3 marks in euchromatic regions. Here we show in collaboration with scientists from University Toronto (Canada) that the triple Tudor domain of SETDB1 binds histone H3 tails containing K14 acetylation combined with K9 methylation, and that the K9me/K14ac modification defines a novel bivalent chromatin state. Structural analyses revealed that peptide binding and K14ac recognition occurs at the interface between Tudor domains 2 and 3. Strikingly, a pocket switch mechanism was observed, because K9me1 or K9me2 is preferentially recognized by the aromatic cage of TD3, while K9me3 selectively binds to TD2. Genomic analyses show that K9me3/K14ac is enriched at SETDB1 binding sites overlapping with LINE elements, suggesting that recruitment of the SETDB1 complex to K14ac/K9me regions has a role in silencing of active genomic regions.