title: Cell-cycle control of developmentally regulated transcription factors accounts for heterogeneity in human pluripotent cells.
abstract: Heterogeneity within pluripotent stem cell (PSC) populations is indicative of dynamic changes that occur when cells drift between different states. Although the role of metastability in PSCs is unclear, it appears to reflect heterogeneity in cell signaling. Using the Fucci cell-cycle indicator system, we show that elevated expression of developmental regulators in G1 is a major determinant of heterogeneity in human embryonic stem cells. Although signaling pathways remain active throughout the cell cycle, their contribution to heterogeneous gene expression is restricted to G1. Surprisingly, we identify dramatic changes in the levels of global 5-hydroxymethylcytosine, an unanticipated source of epigenetic heterogeneity that is tightly linked to cell-cycle progression and the expression of developmental regulators. When we evaluated gene expression in differentiating cells, we found that cell-cycle regulation of developmental regulators was maintained during lineage specification. Cell-cycle regulation of developmentally regulated transcription factors is therefore an inherent feature of the mechanisms underpinning differentiation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
authors.forename: Amar M
authors.initials: AM
authors.lastname: Singh
authors.affiliation: Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
authors.forename: James
authors.initials: J
authors.lastname: Chappell
authors.affiliation: Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Trost
authors.affiliation: Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Vanderbilt Flow Cytometry Shared Resource, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Brittany K
authors.initials: BK
authors.lastname: Matlock
authors.affiliation: Vanderbilt Flow Cytometry Shared Resource, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Weller
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, 1518 Clifton Road, Atlanta, GA 30322, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
authors.forename: Shaying
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dalton
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D018929:Cell Culture Techniques; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D014157:Transcription Factors; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine