Histone H3 lysine 9 di-methylation mediates transcription regulation on damaged chromatin

Abstract

DNA double-strand breaks (DSBs) trigger transient halting of transcription activity in the vicinity during the repair process to protect genomic integrity, a process coined as DSB-induced transcription silencing in cis (DISC). Timely suppression and restoration of local transcription is an integral DNA damage response (DDR) process yet to be fully understood. Previously, the DYRK1B-EHMT2 pathway was identified as a novel effector of DISC. Briefly, the DYRK1B kinase phosphorylates histone methyltransferase EHTM2 to promote its recruitment to the damaged chromatin, which in turn suppresses local gene transcription. However, the downstream target(s) of the DYRK1B-EHMT2 axis has yet to be discovered. In addition, while considerable progress has been made in understanding how transcription repression is mediated, little is known about how transcription resumes once repair is complete. Here, we reveal that EHMT2 catalyzes di-methylation on Histone H3 lysine residue 9 (H3K9me2), a transcriptionally repressive epigenetic modification, to suppress transcription on DSB-bearing chromatin. Furthermore, we show that PHF8, an H3K9me2 demethylase, is necessary for the timely resolution of H3K9me2 on damaged chromatin and facilitates the resumption of transcription following repair in a manner that is functionally uncoupled from the DSB repair process. Moreover, we identify that PHF8 promotes the transcription recovery of rDNA after nucleolar DSB induction and repair. Taken together, our findings propose a delicate interplay between EHMT2 and PHF8 that regulates DSB-associated H3K9me2 dynamics that control transcription activity during DNA damage responses, which is key to preserving genomic integrity and cellular identity.