Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation

Kim Theilgaard-Mönch (), Sachin Pundhir, Kristian Reckzeh, Jinyu Su, Marta Tapia, Benjamin Furtwängler, Johan Jendholm, Janus Schou Jakobsen, Marie Sigurd Hasemann, Kasper Jermiin Knudsen, Jack Bernard Cowland, Anna Fossum, Erwin Schoof, Mikkel Bruhn Schuster and Bo T. Porse ()
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Kim Theilgaard-Mönch: University of Copenhagen
Sachin Pundhir: University of Copenhagen
Kristian Reckzeh: University of Copenhagen
Jinyu Su: University of Copenhagen
Marta Tapia: University of Copenhagen
Benjamin Furtwängler: University of Copenhagen
Johan Jendholm: University of Copenhagen
Janus Schou Jakobsen: University of Copenhagen
Marie Sigurd Hasemann: University of Copenhagen
Kasper Jermiin Knudsen: University of Copenhagen
Jack Bernard Cowland: Rigshospitalet
Anna Fossum: University of Copenhagen
Erwin Schoof: University of Copenhagen
Mikkel Bruhn Schuster: University of Copenhagen
Bo T. Porse: University of Copenhagen

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues, and requires the coordinated induction of lineage-specific transcriptional programs and cell cycle withdrawal. To understand the underlying regulatory mechanisms of this fundamental process, we investigated how the tissue-specific transcription factors, CEBPA and CEBPE, coordinate cell cycle exit and lineage-specification in vivo during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-specification by launching an enhancer-primed differentiation program and direct activation of CEBPE expression. Subsequently, CEBPE confers promoter-driven cell cycle exit by sequential repression of MYC target gene expression at the G1/S transition and E2F-meditated G2/M gene expression, as well as by the up-regulation of Cdk1/2/4 inhibitors. Following cell cycle exit, CEBPE unleashes the CEBPA-primed differentiation program to generate mature granulocytes. These findings highlight how tissue-specific transcription factors coordinate cell cycle exit with differentiation through the use of distinct gene regulatory elements.

Date: 2022
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DOI: 10.1038/s41467-022-31332-1

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