摘要：SummaryTranscriptional fidelity depends on accurate promoter selection and initiation from the correct sites. In yeast, H3K36me3-mediated recruitment of the Rpd3S HDAC complex to gene bodies suppresses spurious transcription initiation. Here we describe an equivalent pathway in metazoans. PWWP2A/B is an H3K36me3 reader that forms a stable complex with HDAC1/2. We used CAGE-seq to profile all transcription initiation sites in wild-type mESCs and cells lacking PWWP2A/B. Loss of PWWP2A/B enhances spurious initiation from intragenic sites present in wild-type mESCs, and this effect is associated with increased levels of initiating Pol-II and histone acetylation. Spurious initiation events inPwwp2a/bDKO mESCs do not overlap in genomic location or chromatin features with spurious sites that arise inDnmt3bKO mESCs, previously reported to function in the suppression of intragenic transcriptional initiation, suggesting these pathways function cooperatively in maintaining the fidelity of transcription initiation in metazoans.Graphical AbstractDisplay OmittedHighlights•Loss of PWWP2A/B leads to increased levels of spurious transcription initiation•Spurious TSS sites are predominantly in the gene bodies of highly expressed genes•Spurious sites are marked with increased histone acetylation and initiating Pol II•PWWP2-spurious TSSs are distinct from those caused by DNMT3B lossMolecular Biology; Molecular Mechanism of Gene Regulation; Stem Cells Research
