Ground State Conditions Induce Rapid Reorganization of Core Pluripotency Factor Binding before Global Epigenetic Reprogramming

Christina Galonska; Michael J Ziller; Rahul Karnik; Alexander Meissner

doi:10.1016/j.stem.2015.07.005

Ground State Conditions Induce Rapid Reorganization of Core Pluripotency Factor Binding before Global Epigenetic Reprogramming

Cell Stem Cell. 2015 Oct 1;17(4):462-70. doi: 10.1016/j.stem.2015.07.005. Epub 2015 Jul 30.

Authors

Christina Galonska¹, Michael J Ziller¹, Rahul Karnik¹, Alexander Meissner²

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: alexander_meissner@harvard.edu.

Abstract

Mouse embryonic stem cells (mESCs) cultured under serum/LIF conditions exhibit heterogeneous expression of pluripotency-associated factors that can be overcome by two inhibitors (2i) of the MEK and GSK3 pathways. Several studies have shown that the "ground state" induced by 2i is characterized by global hypomethylation and specific transcriptional profiles, but little is known about the contributing effectors. Here we show that 2i conditions rapidly alter the global binding landscape of OCT4, SOX2, and NANOG. The dynamic binding influences enhancer activity and shows enrichment for regulators linked to Wnt and Erk signaling. Epigenomic characterization provided limited insights to the immediate transcriptional dynamics, suggesting that these are likely more secondary effects. Likewise, loss of the PRC2 component EED to prevent H3K27me3 deposition had minimal effect on the transcriptome, implying that it is largely dispensable for continued repression of bivalent genes and de novo silencing in 2i.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Enzyme Inhibitors / pharmacology
Epigenesis, Genetic*
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / genetics
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Jumonji Domain-Containing Histone Demethylases / genetics
MAP Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Kinase 1 / genetics
Mice
Mouse Embryonic Stem Cells / physiology*
Nanog Homeobox Protein
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Polycomb Repressive Complex 2 / genetics
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism
Transcriptome

Substances

Eed protein, mouse
Enzyme Inhibitors
Homeodomain Proteins
Nanog Homeobox Protein
Nanog protein, mouse
Octamer Transcription Factor-3
Pou5f1 protein, mouse
SOXB1 Transcription Factors
Sox2 protein, mouse
Jumonji Domain-Containing Histone Demethylases
Kdm6b protein, mouse
Polycomb Repressive Complex 2
Glycogen Synthase Kinase 3
MAP Kinase Kinase 1

Associated data

GEO/GSE56312

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding