Transcription factor-driven coordination of cell cycle exit and specification of cell identify during granulocytic differentiation [RNA-Seq]

Differentiation of multipotent stem cells into mature cells is fundamental for development and homeostasis of mammalian tissues. However, how this temporal process of cell cycle exit and induction of lineage-specific transcription programs is coordinated remains largely unknown. To understand the underlying mechanisms, we investigated how the tissue-specific transcription factors CEBPA and CEBPE coordinate cell cycle exit and lineage-specification during granulocytic differentiation. We demonstrate that CEBPA promotes lineage-commitment 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 terminal differentiation through the use of distinct gene regulatory elements. Examined transcriptome of different populations along granulocytic and monocytic lineage, along with four populations (GP, PM, MY1+2 and MM) for which transcriptiome upon CEBPE KO was also examined.