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

TY - JOUR

T1 - PTBP1-activated co-transcriptional splicing controls epigenetic status of pluripotent stem cells

AU - Iannone, Camilla

AU - Kainov, Yaroslav

AU - Zhuravskaya, Anna

AU - Hamid, Fursham

AU - Nojima, Takayuki

AU - Makeyev, Eugene

N1 - Funding Information: We thank Nicholas Proudfoot and Snezhka Oliferenko for valuable discussions, Simon Engledow for the help with high-throughput sequencing, and Masato Kanemaki, Michael Kyba, Christopher Smith, and Feng Zhang for reagents. This work was supported by the Biotechnology and Biological Sciences Research Council ( BB/M001199/1 , BB/M007103/1 , and BB/V006258/1 ) and the European Commission ( H2020-MSCA-IF-2016 , project ID 751739, and H2020-MSCA-RISE-2016 , project ID 734791). TN is supported by MEXT/JSPS Kakenhi ( 19K24692 ) and JST FOREST program ( JPMJFR2050 ). Publisher Copyright: © 2022 The Author(s)

PY - 2023/1/19

Y1 - 2023/1/19

N2 - 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.

AB - 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.

KW - co-transcriptional splicing

KW - DNMT3B

KW - intron retention

KW - neuronal differentiation

KW - nonsense-mediated decay

KW - PTBP1

UR - http://www.scopus.com/inward/record.url?scp=85146283549&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2022.12.014

DO - 10.1016/j.molcel.2022.12.014

M3 - Article

C2 - 36626906

AN - SCOPUS:85146283549

SN - 1097-2765

VL - 83

SP - 203-218.e9

JO - MOLECULAR CELL

JF - MOLECULAR CELL

IS - 2

ER -