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Epidermal progenitors suppress GRHL3-mediated differentiation through intronic polyadenylation promoted by CPSF-HNRNPA3 collaboration

Author

Listed:
  • Xin Chen

    (Northwestern University)

  • Sarah M. Lloyd

    (Northwestern University)

  • Junghun Kweon

    (Northwestern University)

  • Giovanni M. Gamalong

    (Northwestern University)

  • Xiaomin Bao

    (Northwestern University
    Northwestern University
    Northwestern University)

Abstract

In self-renewing somatic tissue such as skin epidermis, terminal differentiation genes must be suppressed in progenitors to sustain regenerative capacity. Here we show that hundreds of intronic polyadenylation (IpA) sites are differentially used during keratinocyte differentiation, which is accompanied by downregulation of the Cleavage and Polyadenylation Specificity Factor (CPSF) complex. Sustained CPSF expression in undifferentiated keratinocytes requires the contribution from the transcription factor MYC. In keratinocytes cultured in undifferentiation condition, CSPF knockdown induces premature differentiation and partially affects dynamically used IpA sites. These sites include an IpA site located in the first intron of the differentiation activator GRHL3. CRISPR knockout of GRHL3 IpA increased full-length GRHL3 mRNA expression. Using a targeted genetic screen, we identify that HNRNPA3 interacts with CPSF and enhances GRHL3 IpA. Our data suggest a model where the interaction between CPSF and RNA-binding proteins, such as HNRNPA3, promotes site-specific IpA and suppresses premature differentiation in progenitors.

Suggested Citation

  • Xin Chen & Sarah M. Lloyd & Junghun Kweon & Giovanni M. Gamalong & Xiaomin Bao, 2021. "Epidermal progenitors suppress GRHL3-mediated differentiation through intronic polyadenylation promoted by CPSF-HNRNPA3 collaboration," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20674-3
    DOI: 10.1038/s41467-020-20674-3
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    Cited by:

    1. Sarah M. Lloyd & Daniel B. Leon & Mari O. Brady & Deborah Rodriguez & Madison P. McReynolds & Junghun Kweon & Amy E. Neely & Laura A. Blumensaadt & Patric J. Ho & Xiaomin Bao, 2022. "CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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