Cell-Cycle Control of Developmentally Regulated Transcription Factors Accounts for Heterogeneity in Human Pluripotent Cells

• Type of Material: Article
• Authors: Amar M. Singh, University of Georgia; James Chappell, University of Georgia; Robert Trost, University of Georgia; Li Lin, Emory University; Tao Wang, Emory University; Jie Tang, University of Georgia; Hao Wu, Emory University; Shaying Zhao, University of Georgia; Peng Jin, Emory University; Stephen Dalton, University of Georgia
• Language: English
• Date: 2013-12-17
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2013 The Authors.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.stemcr.2013.10.009
• Title of Journal or Parent Work: Stem Cell Reports
• ISSN: 2213-6711
• Volume: 1
• Issue: 6
• Start Page: 532
• End Page: 544
• Grant/Funding Information: This work was supported by grants to S.D. from the National Institute of Child Health and Human Development (HD049647) and the National Institute for General Medical Sciences (GM75334).
• Keywords: DEFINITIVE ENDODERM; DIFFERENTIATION; EMBRYONIC STEM-CELLS; Cell & Tissue Engineering; G1 PHASE; Life Sciences & Biomedicine; GROUND-STATE; Cell Biology; RNA-SEQ; Science & Technology; EXPRESSION; SELF-RENEWAL; EQUILIBRIUM; PRIMITIVE ENDODERM
• Research Categories: Biology, Bioinformatics; Chemistry, Biochemistry; Biology, Genetics

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 ex pression 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.