Cell-Cycle Control of Bivalent Epigenetic Domains Regulates the Exit from Pluripotency

Abstract

SummaryHere we show that bivalent domains and chromosome architecture for bivalent genes are dynamically regulated during the cell cycle in human pluripotent cells. Central to this is the transient increase in H3K4-trimethylation at developmental genes during G1, thereby creating a “window of opportunity” for cell-fate specification. This mechanism is controlled by CDK2-dependent phosphorylation of the MLL2 (KMT2B) histone methyl-transferase, which facilitates its recruitment to developmental genes in G1. MLL2 binding is required for changes in chromosome architecture around developmental genes and establishes promoter-enhancer looping interactions in a cell-cycle-dependent manner. These cell-cycle-regulated loops are shown to be essential for activation of bivalent genes and pluripotency exit. These findings demonstrate that bivalent domains are established to control the cell-cycle-dependent activation of developmental genes so that differentiation initiates from the G1 phase.

Cycling through developmental decisions: how cell cycle dynamics control pluripotency, differentiation and reprogramming

“…This is consistent with earlier reports showing that developmental genes are primed for transcription in G1 phase (Singh et al, 2013(Singh et al, , 2015. Increased transcription as cells transition into G1 phase is thought to localize at genomic regions pre-marked with H3K27ac.…”

“…However, residual amounts of histone acetylation, which bookmarks a select group of gene promoters, has also been reported (Dey et al, 2009;Kouskouti and Talianidis, 2005;Valls et al, 2005;Zhao et al, 2011). Despite many repressive marks such as H3K9me3 and H3K27me3 being retained in mitotic chromatin (Follmer et al, 2012;Li et al, 2006;Peters et al, 2002;Singh et al, 2015), the functional proteins -known as 'writers' and 'readers' -that deposit and associate with these marks, such as SUV39H1, HP1 (HP1 gamma also known as CBX3) and BMI1, are generally excluded from mitotic chromatin (Egli et al, 2008;Kellum et al, 1995;Minc et al, 1999;Voncken et al, 1999). Histone modifications during mitosis have been reviewed in more detail elsewhere (Wang and Higgins, 2013).…”

“…An additional report using the Fucci system to dissect cell cycle events has since been published, focusing on the links between epigenetic events and the cell cycle (Singh et al, 2015). In this study, Singh and co-workers characterized the epigenetic changes that occur in self-renewing hPSCs and found that H3K4 trimethylation within bivalent domains of developmental genes Developmental genes are 'bookmarked' epigenetically in mitosis for rapid activation in the upcoming G1 phase.…”

“…In summary, a combination of epigenetics, chromosome architecture and transcription factor recruitment appears to be involved in priming developmental genes for G1-specific differentiation. CDK activity has been implicated in control of these regulatory steps (Pauklin and Vallier, 2013;Singh et al, 2015) (Fig. 2), establishing a link between cell fate decisions and the cell cycle machinery.…”

The matrix protein Tiggrin regulates plasmatocyte maturation inDrosophilalarva

“…9). In pluripotent stem cells, cells in G 1 phase are more likely to undergo differentiation Calder et al, 2013;Coronado et al, 2013;Sela et al, 2012), possibly owing to cell cycle stagedependent expression of key developmental regulators (Pauklin and Vallier, 2013;Singh et al, 2015). Perhaps our data showing that Wee1 and Stg regulate Tig expression is an example of G 2 phasedependent developmental regulation.…”