Transcription factor-driven coordination of cell cycle exit and specification of cell identify during granulocytic differentiation [ChIP-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. Overall design: ChIP-seq of CEBPE in WT and CEBPA KO MY1+2, MM, BC and PMN populations of granulocytic differentiation. ChIP-seqs were performed in biological duplicates.