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Author Notes:

Corresponding author ; Email: sdalton@uga.edu

A.M.S. and Y.S. are co-first authors.

A.M.S. and Y.S. designed, performed, and analyzed the experiments and wrote the manuscript.

L.L., W.Z., S.Z., and Z.Q. performed bioinformatics analyses.

T.W. performed and analyzed experiments.

S.D. oversaw the project, designed and analyzed the experiments, and wrote the manuscript.

We thank Julie Nelson for assistance with FACS.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell & Tissue Engineering
  • Cell Biology
  • EMBRYONIC STEM-CELLS
  • DEVELOPMENTAL REGULATORS
  • TRANSCRIPTION FACTORS
  • CHROMATIN STATE
  • DIFFERENTIATION
  • PROMOTERS
  • G1
  • PROPENSITY
  • COMPLEXES
  • PROTEINS

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

Journal Title:

Stem Cell Reports

Volume:

Volume 5, Number 3

Publisher:

, Pages 323-336

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015 The Authors.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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