A hyperactive transcriptional state marks genome reactivation at the mitosis–G1 transition

Abstract

During mitosis, RNA polymerase II (Pol II) and many transcription factors dissociate from chromatin, and transcription ceases globally. Transcription is known to restart in bulk by telophase, but whether de novo transcription at the mitosis-G1 transition is in any way distinct from later in interphase remains unknown. We tracked Pol II occupancy genome-wide in mammalian cells progressing from mitosis through late G1. Unexpectedly, during the earliest rounds of transcription at the mitosis-G1 transition, ∼50% of active genes and distal enhancers exhibit a spike in transcription, exceeding levels observed later in G1 phase. Enhancer-promoter chromatin contacts are depleted during mitosis and restored rapidly upon G1 entry but do not spike. Of the chromatin-associated features examined, histone H3 Lys27 acetylation levels at individual loci in mitosis best predict the mitosis-G1 transcriptional spike. Single-molecule RNA imaging supports that the mitosis-G1 transcriptional spike can constitute the maximum transcriptional activity per DNA copy throughout the cell division cycle. The transcriptional spike occurs heterogeneously and propagates to cell-to-cell differences in mature mRNA expression. Our results raise the possibility that passage through the mitosis-G1 transition might predispose cells to diverge in gene expression states.

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

“…The idea that the transition from mitosis to G1 phase might establish conditions in which switching of lineage-specific transcriptional programs is possible is supported by studies showing that this window of the cell cycle represents a hyperactive, dynamic transcriptional state (Hsiung et al, 2016). 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. This hypertranscriptional activity is not uniform and might also account for cellular heterogeneity (Hsiung et al, 2016). A recent study has revealed another interesting connection between exit from pluripotency and early cell fate decisions, this time involving S phase and G2 phase.…”

A role for mitotic bookmarking of SOX2 in pluripotency and differentiation

“…This hypothesis was fueled by experimental evidence of mitotic bookmarking as a mechanism for rapid gene reactivation in G1 (Blobel et al 2009;Dey et al 2009;Kadauke et al 2012) and thus potentially contributing to robust maintenance of cell type-specific gene expression programs after cell division. However, recent studies have challenged the role of binding to specific DNA sites during mitosis for rapid transcriptional reactivation of targeted genes (Caravaca et al 2013;Hsiung et al 2016), and, most importantly, the functional relevance of mitotic bookmarking in cell fate decision making has not been demonstrated so far. Our study reveals a key time window for the action of SOX2 on cell fate decisions, which temporally overlaps with its mitotic bookmarking activity and the re-establishment of transcriptional activity in newly divided cells (Hsiung et al 2016).…”

“…However, recent studies have challenged the role of binding to specific DNA sites during mitosis for rapid transcriptional reactivation of targeted genes (Caravaca et al 2013;Hsiung et al 2016), and, most importantly, the functional relevance of mitotic bookmarking in cell fate decision making has not been demonstrated so far. Our study reveals a key time window for the action of SOX2 on cell fate decisions, which temporally overlaps with its mitotic bookmarking activity and the re-establishment of transcriptional activity in newly divided cells (Hsiung et al 2016). Interestingly, the functional importance of SOX2 at the M-G1 transition differed across the cell fate decisions that we studied.…”

“…In contrast to GATA1 (Kadauke et al 2012), RBPJ (Lake et al 2014), or MLL (Blobel et al 2009) but similar to FOXA1 (Caravaca et al 2013), we did not find enrichment of a particular class of genes bound by SOX2 during mitosis. The functional relevance of the sites specifically bound on mitotic chromosomes remains unclear, and there appears to be no quantitative difference in early G1 transcriptional activity of genes bound by FOXA1 or GATA1 in mitosis compared with genes bound in interphase only (Caravaca et al 2013;Hsiung et al 2016). Interestingly, nonspecific binding to mitotic chromosomes was also shown to regulate transcriptional reactivation in G1 (Caravaca et al 2013).…”