Mechanism of maintenance and establishment of repression by the Mtg16 tumor suppressor [CUT&RUN, ChIP-Seq]

The MTG family of transcriptional corepressors are frequent targets of chromosomal translocations and deletions in cancer, yet the mechanisms underlying tumor suppression are unclear. We employed a chemical-genetic approach to investigate the molecular mechanism of Mtg16-mediated repression. Analysis of nascent transcription revealed that Mtg16 is required to repress hundreds of genes and enhancers, including the oncogenes Myb and Gfi1b. Because Mtg16 tightly regulated its own transcription, this model yielded a rapid “on/off/on” switch for Mtg16, providing a unique opportunity to study maintenance and establishment of repression within the same system. Mtg16 directly opposed histone acetylation at regulated loci, but analysis of H3K27ac revealed that changes in this mark correlated better with Mtg16 itself than with transcriptional activity. Importantly, both the relationship between Mtg16 and Class I HDAC activity and Mtg16-mediated re-establishment of repression were dependent target transcription. We propose that Mtg16 acts as a transcription-sensitive damper at highly accessible loci.