Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 13, Pages 3473-3478Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1617636114
Keywords
GRO-seq; nascent RNA; transcriptional regulation; epigenetics; cell cycle
Categories
Funding
- National Natural Science Foundation of China [31329003]
- Princess Margaret Cancer Foundation
- Canada Foundation for Innovation
- Ontario Research Fund [CFI32372]
- Natural Sciences and Engineering Research Council of Canada [498706]
- NIH [1R01GM099409]
- US Public Health Service [R01CA63113, R01CA173023]
- German National Academy of Sciences Leopoldina Fellowship
- Office of Management, Information, and Research (OMIR) Early Researcher Award
- Terry Fox New Investigator Award
- Canadian Institutes of Health Research (CIHR) New Investigator Salary Award
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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.
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