Transcriptional landscape of the human cell cycle

Abstract

Steady-state gene expression across the cell cycle has been studied extensively. However, transcriptional gene regulation and the dynamics of histone modification at different cell-cycle stages are largely unknown. By applying a combination of global nuclear run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and histone-modification Chip sequencing (ChIP-seq), we depicted a comprehensive transcriptional landscape at the G0/G1, G1/S, and M phases of breast cancer MCF-7 cells. Importantly, GRO-seq and RNA-seq analysis identified different cell-cycle-regulated genes, suggesting a lag between transcription and steady-state expression during the cell cycle. Interestingly, we identified genes actively transcribed at early M phase that are longer in length and have low expression and are accompanied by a global increase in active histone 3 lysine 4 methylation (H3K4me2) and histone 3 lysine 27 acetylation (H3K27ac) modifications. In addition, we identified 2,440 cell-cycle-regulated enhancer RNAs (eRNAs) that are strongly associated with differential active transcription but not with stable expression levels across the cell cycle. Motif analysis of dynamic eRNAs predicted Kruppel-like factor 4 (KLF4) as a key regulator of G1/S transition, and this identification was validated experimentally. Taken together, our combined analysis characterized the transcriptional and histone-modification profile of the human cell cycle and identified dynamic transcriptional signatures across the cell cycle.

Widespread Mitotic Bookmarking by Histone Marks and Transcription Factors in Pluripotent Stem Cells

“…A potential explanation would be that these mitotic-specific enhancer elements play a role in maintaining or inducing transcriptional activity of selected genes during mitosis, a possibility that could be addressed by nascent RNA sequencing experiments. Of note, although global transcriptional shut down during mitosis is well documented, an increasing number of studies report subsets of genes that “escape” this silencing (Halley-Stott et al, 2014; Liang et al, 2015; Liu, et al, 2017; Sciortino et al, 2001). …”

Study of mitotic chromatin supports a model of bookmarking by histone modifications and reveals nucleosome deposition patterns

“…Conversely, most H3K27ac genome-wide studies describe a degree of locus specificity in the maintenance of H3K27ac during mitosis (Hsiung et al 2016;Li et al 2017;Liu et al 2017a;Liu et al 2017b).…”

Mitotic transcription and waves of gene reactivation during mitotic exit

“…The study also mapped non-polyadenylated, chromatin-associated RNAs from prometaphase cells, but it was unclear whether these RNAs were transcribed during mitosis or, as suggested by the authors, at the G2/M transition. A study of pulse-labeled transcripts in arrested MCF-7 human breast cancer cells used nuclear isolation for BrUTP labeling and hence did not appear to be assessing mitotic cells (20). …”