Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation: In memoriam Professor Niels Borregaard

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, Bo T Porse

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.

OriginalsprogEngelsk
TidsskriftNature Communications
Vol/bind13
Udgave nummer1
Sider (fra-til)3595
ISSN2041-1722
DOI
StatusUdgivet - 23 jun. 2022

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