PTBP1-activated co-transcriptional splicing controls epigenetic status of pluripotent stem cells

Camilla Iannone, Yaroslav Kainov, Anna Zhuravskaya, Fursham Hamid, Takayuki Nojima, Eugene Makeyev*

*Corresponding author for this work

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Many spliceosomal introns are excised from nascent transcripts emerging from RNA polymerase II (Pol II). The extent of cell-type specific regulation and possible functions of such co-transcriptional events remain poorly understood. We examined the role of the RNA-binding protein PTBP1 in this process using an acute depletion approach followed by the analysis of chromatin- and Pol II-associated transcripts. We show that PTBP1 activates co-transcriptional excision of hundreds of introns, a surprising effect given that this protein is known to promote intron retention. Importantly, some co-transcriptionally activated introns fail to complete their splicing without PTBP1. In a striking example, retention of a PTBP1-dependent intron triggers nonsense-mediated decay of transcripts encoding DNA methyltransferase DNMT3B. We provide evidence that this regulation facilitates the natural decline in DNMT3B levels in developing neurons and protects differentiation-specific genes from ectopic methylation. Thus, PTBP1-activated co-transcriptional splicing is a widespread phenomenon mediating epigenetic control of cellular identity.
Original languageEnglish
Publication statusAccepted/In press - 13 Dec 2022


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