title: 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.
authors.affiliation: 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.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China.|Department of Bioinformatics, School of Life Sciences, Tongji University, Shanghai 200092, China.|Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
authors.forename: Sujun
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Bioinformatics, School of Life Sciences, Tongji University, Shanghai 200092, China.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.|Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02215.
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada.
authors.forename: Fraser
authors.initials: F
authors.lastname: Soares
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215.
authors.forename: Martin
authors.initials: M
authors.lastname: Fischer
authors.affiliation: 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.
authors.forename: Feilong
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Bioinformatics, School of Life Sciences, Tongji University, Shanghai 200092, China.|Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.|Program in Cellular and Molecular Medicine, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Molecular and Human Genetics; Baylor College of Medicine Houston, TX 77030.
authors.forename: Charles
authors.initials: C
authors.lastname: Lin
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02215.
authors.forename: Clifford
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215.
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215; myles_brown@dfci.harvard.edu xsliu@jimmy.harvard.edu hansenhe@uhnresearch.ca.|Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215; myles_brown@dfci.harvard.edu xsliu@jimmy.harvard.edu hansenhe@uhnresearch.ca.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA 02215.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada; myles_brown@dfci.harvard.edu xsliu@jimmy.harvard.edu hansenhe@uhnresearch.ca.|Department of Medical Biophysics, University of Toronto, Toronto, ON M5G1L7, Canada.
authors.forename: Housheng Hansen
authors.identifier: 0000-0003-2898-3363
authors.initials: HH
authors.lastname: He
mesh_terms: D002453:Cell Cycle; D047369:Chromatin Immunoprecipitation; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D061986:MCF-7 Cells; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: D006657:Histones; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4
keywords: GRO-seq; cell cycle; epigenetics; nascent RNA; transcriptional regulation