Abstract
Pluripotency transcription programs by core transcription factors (CTFs) might be reset during M/G1 transition to maintain the pluripotency of embryonic stem cells (ESCs). However, little is known about how CTFs are governed during cell cycle progression. Here, we demonstrate that the regulation of Oct4 by Aurora kinase b (Aurkb)/protein phosphatase 1 (PP1) during the cell cycle is important for resetting Oct4 to pluripotency and cell cycle genes in determining the identity of ESCs. Aurkb phosphorylates Oct4(S229) during G2/M phase, leading to the dissociation of Oct4 from chromatin, whereas PP1 binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition, which resets Oct4-driven transcription for pluripotency and the cell cycle. Aurkb phosphor-mimetic and PP1 binding-deficient mutations in Oct4 alter the cell cycle, effect the loss of pluripotency in ESCs, and decrease the efficiency of somatic cell reprogramming. Our findings provide evidence that the cell cycle is linked directly to pluripotency programs in ESCs.
Highlights
Embryonic stem cells (ESCs) have unique transcriptional programs for self-renewal and pluripotency which differentiates into all types of cells
We propose that the recycling of Oct4 by Aurora kinase b (Aurkb)/phosphatase 1 (PP1) over time and by location is pivotal for the transcriptional resetting of Oct4 during entry in to the subsequent G1 phase, maintaining ESC pluripotency and cell cycle progression (Figure 8)
We have demonstrated that Oct4, a master pluripotency transcription factor, is spatiotemporally regulated by the Aurkb-PP1 axis during the cell cycle
Summary
Embryonic stem cells (ESCs) have unique transcriptional programs for self-renewal and pluripotency which differentiates into all types of cells. Core transcription factors—Oct, Sox, Nanog (OSN)— govern such pluripotency transcriptional programs (Jaenisch and Young, 2008; Young, 2011). ESCs grow rapidly and undergo an unusual cell cycle, characterized by a very short G1 phase and a long S phase in mouse and human (Kapinas et al, 2013; Savatier et al, 1994; White and Dalton, 2005). The duration of G1 in mouse ESCs and human ESCs determines their fate with regard to differentiation and pluripotency (Coronado et al, 2013; Mummery et al, 1987; Pauklin and Vallier, 2013). Cell cycle regulation in ESCs should be linked to pluripotency in maintaining ESC identity
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