Cell-Cycle Control of Bivalent Epigenetic Domains Regulates the Exit from Pluripotency

• Type of Material: Article
• Authors: Amar M. Singh, University of Georgia; Yuhua Sun, University of Georgia; Li Li, University of Georgia; Wenjuan Zhang, University of Georgia; Tianming Wu, University of Georgia; Shaying Zhao, University of Georgia; Zhaohui Qin, Emory University; Stephen Dalton, University of Georgia
• Language: English
• Date: 2015-09-08
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2015 The Authors.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.stemcr.2015.07.005
• Title of Journal or Parent Work: Stem Cell Reports
• ISSN: 2213-6711
• Volume: 5
• Issue: 3
• Start Page: 323
• End Page: 336
• 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: Cell & Tissue Engineering; PROTEINS; COMPLEXES; DEVELOPMENTAL REGULATORS; EMBRYONIC STEM-CELLS; CHROMATIN STATE; Life Sciences & Biomedicine; TRANSCRIPTION FACTORS; Science & Technology; Cell Biology; PROMOTERS; PROPENSITY; G1; DIFFERENTIATION
• Research Categories: Biology, Genetics; Biology, Cell; Biology, Bioinformatics

Abstract

Summary Here we show that bivalent domains and chromosome architecture for bivalent genes are dynamically regulated during the cell cycle in human pluripotent cells. Central to this is the transient increase in H3K4-trimethylation at developmental genes during G1, thereby creating a "window of opportunity" for cell-fate specification. This mechanism is controlled by CDK2-dependent phosphorylation of the MLL2 (KMT2B) histone methyl-transferase, which facilitates its recruitment to developmental genes in G1. MLL2 binding is required for changes in chromosome architecture around developmental genes and establishes promoter-enhancer looping interactions in a cell-cycle-dependent manner. These cell-cycle-regulated loops are shown to be essential for activation of bivalent genes and pluripotency exit. These findings demonstrate that bivalent domains are established to control the cell-cycle-dependent activation of developmental genes so that differentiation initiates from the G1 phase.In this report, Dalton and colleagues show that developmental genes are primed for activation in G1 phase of the cell cycle by a mechanism requiring convergence of the cell-cycle machinery with cell signaling pathways. This priming mechanism involves the establishment of bivalent epigenetic domains and dynamic changes in chromosome architecture around developmental genes.