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Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):3473-3478. doi: 10.1073/pnas.1617636114. Epub 2017 Mar 13.

Transcriptional landscape of the human cell cycle.

Liu Y1,2,3, Chen S1,2,4,5, Wang S2,3,6, Soares F4, Fischer M7, Meng F8, Du Z2,3,9, Lin C10, Meyer C3,11, DeCaprio JA7, Brown M12,7, Liu XS12,11, He HH13,5.

Author information

Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China.
Department of Bioinformatics, School of Life Sciences, Tongji University, Shanghai 200092, China.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02215.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215.
State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115.
Department of Molecular and Human Genetics; Baylor College of Medicine Houston, TX 77030.
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02215.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215;
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada;


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.


GRO-seq; cell cycle; epigenetics; nascent RNA; transcriptional regulation

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