Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy [CUT&RUN]
Using a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma and other pediatric high-grade gliomas, we observe a rapid genome-wide reorganization of active chromatin within hours of exposure to therapeutic ionizing radiation. This redistribution facilitates PTEFb-mediated pause-release of Pol II to drive nascent transcriptional induction of canonical DNA damage response programs. Concurrent inhibition of PTEFb imparts a transcription elongation defect, disrupting this chromatin reorganization and blunting transcriptional induction. Functionally, concurrent PTEFb inhibition abrogates key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. Overall design: Phosphorylated RNA polymerase II, Brd4 and ENL CUT&RUN was conducted with the DIPG4 cell line in the presence or absence of AZD or DMSO as control and subjected or not to radiation.