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

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Aug 4

PMID 26235340

Citations 55

Authors

Christina Galonska

Michael J Ziller

Rahul Karnik

Alexander Meissner

Affiliations

Soon will be listed here.

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.

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References

Yeo J, Jiang J, Tan Z, Yim G, Ng J, Goke J . Klf2 is an essential factor that sustains ground state pluripotency. Cell Stem Cell. 2014; 14(6):864-72. DOI: 10.1016/j.stem.2014.04.015. View

Yang S, Kalkan T, Morissroe C, Marks H, Stunnenberg H, Smith A . Otx2 and Oct4 drive early enhancer activation during embryonic stem cell transition from naive pluripotency. Cell Rep. 2014; 7(6):1968-81. PMC: 4074343. DOI: 10.1016/j.celrep.2014.05.037. View

Habibi E, Brinkman A, Arand J, Kroeze L, Kerstens H, Matarese F . Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell. 2013; 13(3):360-9. DOI: 10.1016/j.stem.2013.06.002. View

Galonska C, Smith Z, Meissner A . In Vivo and in vitro dynamics of undifferentiated embryonic cell transcription factor 1. Stem Cell Reports. 2014; 2(3):245-52. PMC: 3964277. DOI: 10.1016/j.stemcr.2014.01.007. View

Leitch H, McEwen K, Turp A, Encheva V, Carroll T, Grabole N . Naive pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol. 2013; 20(3):311-6. PMC: 3591483. DOI: 10.1038/nsmb.2510. View

Koche R, Smith Z, Adli M, Gu H, Ku M, Gnirke A . Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell. 2011; 8(1):96-105. PMC: 3220622. DOI: 10.1016/j.stem.2010.12.001. View

Kim J, Chu J, Shen X, Wang J, Orkin S . An extended transcriptional network for pluripotency of embryonic stem cells. Cell. 2008; 132(6):1049-61. PMC: 3837340. DOI: 10.1016/j.cell.2008.02.039. View

Marks H, Kalkan T, Menafra R, Denissov S, Jones K, Hofemeister H . The transcriptional and epigenomic foundations of ground state pluripotency. Cell. 2012; 149(3):590-604. PMC: 3398752. DOI: 10.1016/j.cell.2012.03.026. View

Silva J, Nichols J, Theunissen T, Guo G, van Oosten A, Barrandon O . Nanog is the gateway to the pluripotent ground state. Cell. 2009; 138(4):722-37. PMC: 3437554. DOI: 10.1016/j.cell.2009.07.039. View

10.

Chen X, Xu H, Yuan P, Fang F, Huss M, Vega V . Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008; 133(6):1106-17. DOI: 10.1016/j.cell.2008.04.043. View

11.

Boyer L, Plath K, Zeitlinger J, Brambrink T, Medeiros L, Lee T . Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006; 441(7091):349-53. DOI: 10.1038/nature04733. View

12.

Cusanovich D, Pavlovic B, Pritchard J, Gilad Y . The functional consequences of variation in transcription factor binding. PLoS Genet. 2014; 10(3):e1004226. PMC: 3945204. DOI: 10.1371/journal.pgen.1004226. View

13.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

14.

Chan Y, Goke J, Ng J, Lu X, Gonzales K, Tan C . Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast. Cell Stem Cell. 2013; 13(6):663-75. DOI: 10.1016/j.stem.2013.11.015. View

15.

Black A, Black J, Azizkhan-Clifford J . Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol. 2001; 188(2):143-60. DOI: 10.1002/jcp.1111. View

16.

Gregg J, Fraizer G . Transcriptional Regulation of EGR1 by EGF and the ERK Signaling Pathway in Prostate Cancer Cells. Genes Cancer. 2012; 2(9):900-9. PMC: 3352154. DOI: 10.1177/1947601911431885. View

17.

Deschamps J, van Nes J . Developmental regulation of the Hox genes during axial morphogenesis in the mouse. Development. 2005; 132(13):2931-42. DOI: 10.1242/dev.01897. View

18.

Loh Y, Wu Q, Chew J, Vega V, Zhang W, Chen X . The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet. 2006; 38(4):431-40. DOI: 10.1038/ng1760. View

19.

Gifford C, Ziller M, Gu H, Trapnell C, Donaghey J, Tsankov A . Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell. 2013; 153(5):1149-63. PMC: 3709577. DOI: 10.1016/j.cell.2013.04.037. View

20.

Montgomery N, Yee D, Chen A, Kalantry S, Chamberlain S, Otte A . The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol. 2005; 15(10):942-7. DOI: 10.1016/j.cub.2005.04.051. View