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.
| Original language | English (US) |
|---|---|
| Article number | 4408 |
| Journal | Nature communications |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
Funding
This work is supported by an NIH K99/R00 Award (R00AR065480) to X.B., an NIH R01 (AR075015) to X.B., a Research Scholar Grant (RSG-21-018-01-DDC) from the American Cancer Society to X.B., the Searle Leadership Fund to X.B., the Northwestern Skin Disease Research Center Pilot & Feasibility Award to X.B., the Basic Insights Award from Northwestern Cancer Center to X.B., a NUCATS Pilot Award to X.B., an NIH CMBD training grant (T32GM008061) to S.M.L. as a trainee, a Northwestern Presidential Fellowship to S.M.L., Northwestern Summer Undergraduate Research Grants (L.A.B., M.O.B., M.P.M., D.B.L., D.R.), Northwestern Academic Year Undergraduate Research Grants (M.O.B., M.P.M., D.B.L.), and Weinberg College Summer Research Grants (D.B.L., D.R., L.A.B., M.O.B.). We appreciate the support from the Skin Biology and Diseases Resource-based Center (SBDRC, P30AR075049) for providing tissues and culture media for this study, and the NUseq facility for providing next-generation sequencing service for this study. We thank Kaiwei Liang, Yuki Aoi, Edwin R. Smith, and Ali Shilatifard for sharing the KL1 and KL2 inhibitors, the AFF1/4 antibodies, as well as a subset of shRNAs used in this study. These reagents were instrumental in making this project possible. We also appreciate the suggestions from the Shilatifard Lab on this project.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy