CDK9 Activity Switch Associated with AFF1 and HEXIM1 Controls Differentiation Initiation from Epidermal Progenitors

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jul 29

PMID 35906225

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

Guo Y, Manteiga J, Henninger J, Sabari B, DallAgnese A, Hannett N . Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature. 2019; 572(7770):543-548. PMC: 6706314. DOI: 10.1038/s41586-019-1464-0. View

Okuyama R, Lefort K, Dotto G . A dynamic model of keratinocyte stem cell renewal and differentiation: role of the p21WAF1/Cip1 and Notch1 signaling pathways. J Investig Dermatol Symp Proc. 2004; 9(3):248-52. DOI: 10.1111/j.1087-0024.2004.09308.x. View

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

Kim D, Paggi J, Park C, Bennett C, Salzberg S . Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019; 37(8):907-915. PMC: 7605509. DOI: 10.1038/s41587-019-0201-4. View

Cui H, Li X, Han C, Wang Q, Wang H, Ding H . The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins. J Biol Chem. 2016; 291(20):10847-57. PMC: 4865929. DOI: 10.1074/jbc.M115.713099. View

Adhikary G, Chew Y, Reece E, Eckert R . PKC-delta and -eta, MEKK-1, MEK-6, MEK-3, and p38-delta are essential mediators of the response of normal human epidermal keratinocytes to differentiating agents. J Invest Dermatol. 2010; 130(8):2017-30. PMC: 3120227. DOI: 10.1038/jid.2010.108. View

Lagha M, Bothma J, Esposito E, Ng S, Stefanik L, Tsui C . Paused Pol II coordinates tissue morphogenesis in the Drosophila embryo. Cell. 2013; 153(5):976-87. PMC: 4257494. DOI: 10.1016/j.cell.2013.04.045. View

Liebig T, Erasmus J, Kalaji R, Davies D, Loirand G, Ridley A . RhoE Is required for keratinocyte differentiation and stratification. Mol Biol Cell. 2008; 20(1):452-63. PMC: 2613104. DOI: 10.1091/mbc.e07-11-1197. View

10.

Quinlan A, Hall I . BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010; 26(6):841-2. PMC: 2832824. DOI: 10.1093/bioinformatics/btq033. View

11.

Yu Z, Lin K, Bhandari A, Spencer J, Xu X, Wang N . The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4. Dev Biol. 2006; 299(1):122-36. DOI: 10.1016/j.ydbio.2006.07.015. View

12.

Zheng B, Aoi Y, Shah A, Iwanaszko M, Das S, Rendleman E . Acute perturbation strategies in interrogating RNA polymerase II elongation factor function in gene expression. Genes Dev. 2021; 35(3-4):273-285. PMC: 7849361. DOI: 10.1101/gad.346106.120. View

13.

Lu X, Zhu X, Li Y, Liu M, Yu B, Wang Y . Multiple P-TEFbs cooperatively regulate the release of promoter-proximally paused RNA polymerase II. Nucleic Acids Res. 2016; 44(14):6853-67. PMC: 5001612. DOI: 10.1093/nar/gkw571. View

14.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

15.

Lin C, Smith E, Takahashi H, Lai K, Martin-Brown S, Florens L . AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010; 37(3):429-37. PMC: 2872029. DOI: 10.1016/j.molcel.2010.01.026. View

16.

Nair M, Teng A, Bilanchone V, Agrawal A, Li B, Dai X . Ovol1 regulates the growth arrest of embryonic epidermal progenitor cells and represses c-myc transcription. J Cell Biol. 2006; 173(2):253-64. PMC: 2063816. DOI: 10.1083/jcb.200508196. View

17.

Truong A, Kretz M, Ridky T, Kimmel R, Khavari P . p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev. 2006; 20(22):3185-97. PMC: 1635152. DOI: 10.1101/gad.1463206. View

18.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

19.

Palazzo E, Kellett M, Cataisson C, Bible P, Bhattacharya S, Sun H . A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation. Cell Death Differ. 2017; 24(4):717-730. PMC: 5384032. DOI: 10.1038/cdd.2017.5. View

20.

Li J, Xu X, Tiwari M, Chen Y, Fuller M, Bansal V . SPT6 promotes epidermal differentiation and blockade of an intestinal-like phenotype through control of transcriptional elongation. Nat Commun. 2021; 12(1):784. PMC: 7862286. DOI: 10.1038/s41467-021-21067-w. View