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CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors

Author

Listed:
  • Sarah M. Lloyd

    (Northwestern University
    Northwestern University)

  • Daniel B. Leon

    (Northwestern University)

  • Mari O. Brady

    (Northwestern University)

  • Deborah Rodriguez

    (Northwestern University)

  • Madison P. McReynolds

    (Northwestern University)

  • Junghun Kweon

    (Northwestern University)

  • Amy E. Neely

    (Northwestern University)

  • Laura A. Blumensaadt

    (Northwestern University)

  • Patric J. Ho

    (Northwestern University)

  • Xiaomin Bao

    (Northwestern University
    Northwestern University
    Northwestern University
    Northwestern University)

Abstract

Progenitors in epithelial tissues, such as human skin epidermis, continuously make fate decisions between self-renewal and differentiation. Here we show that the Super Elongation Complex (SEC) controls progenitor fate decisions by directly suppressing a group of “rapid response” genes, which feature high enrichment of paused Pol II in the progenitor state and robust Pol II elongation in differentiation. SEC’s repressive role is dependent on the AFF1 scaffold, but not AFF4. In the progenitor state, AFF1-SEC associates with the HEXIM1-containing inactive CDK9 to suppress these rapid-response genes. A key rapid-response SEC target is ATF3, which promotes the upregulation of differentiation-activating transcription factors (GRHL3, OVOL1, PRDM1, ZNF750) to advance terminal differentiation. SEC peptidomimetic inhibitors or PKC signaling activates CDK9 and rapidly induces these transcription factors within hours in keratinocytes. Thus, our data suggest that the activity switch of SEC-associated CDK9 underlies the initial processes bifurcating progenitor fates between self-renewal and differentiation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32098-2
    DOI: 10.1038/s41467-022-32098-2
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    References listed on IDEAS

    as
    1. 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.
    2. Yang Eric Guo & John C. Manteiga & Jonathan E. Henninger & Benjamin R. Sabari & Alessandra Dall’Agnese & Nancy M. Hannett & Jan-Hendrik Spille & Lena K. Afeyan & Alicia V. Zamudio & Krishna Shrinivas , 2019. "Pol II phosphorylation regulates a switch between transcriptional and splicing condensates," Nature, Nature, vol. 572(7770), pages 543-548, August.
    3. George L. Sen & Jason A. Reuter & Daniel E. Webster & Lilly Zhu & Paul A. Khavari, 2010. "DNMT1 maintains progenitor function in self-renewing somatic tissue," Nature, Nature, vol. 463(7280), pages 563-567, January.
    4. Shuxiong Wang & Michael L. Drummond & Christian F. Guerrero-Juarez & Eric Tarapore & Adam L. MacLean & Adam R. Stabell & Stephanie C. Wu & Guadalupe Gutierrez & Bao T. That & Claudia A. Benavente & Qi, 2020. "Single cell transcriptomics of human epidermis identifies basal stem cell transition states," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    5. Roberto Bandiera & Rebecca E. Wagner & Thiago Britto-Borges & Christoph Dieterich & Sabine Dietmann & Susanne Bornelöv & Michaela Frye, 2021. "RN7SK small nuclear RNA controls bidirectional transcription of highly expressed gene pairs in skin," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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