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.

多能干细胞分化为成熟细胞是哺乳动物组织发育和稳态的基础，并且需要协调诱导谱系特异性转录程序和细胞周期退出。为了了解这一基本过程的潜在调节机制，我们研究了组织特异性转录因子 CEBPA 和 CEBPE 如何在粒细胞分化过程中协调体内细胞周期退出和谱系特异性。我们证明 CEBPA 通过启动增强子引发的分化程序和直接激活 CEBPE 表达来促进谱系特异性。随后，CEBPE 通过在 G1/S 转变时连续抑制 MYC 靶基因表达和 E2F 介导的 G2/M 基因表达以及通过Cdk1/2/4抑制剂的上调来赋予启动子驱动的细胞周期退出。细胞周期退出后，CEBPE 释放 CEBPA 引发的分化程序以生成成熟粒细胞。这些发现强调了组织特异性转录因子如何通过使用不同的基因调控元件来协调细胞周期退出和分化。