The Transcriptional and Epigenomic Foundations of Ground State Pluripotency

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 May 1

PMID 22541430

Citations 477

Authors

Hendrik Marks

Tuzer Kalkan

Roberta Menafra

Sergey Denissov

Kenneth Jones

Helmut Hofemeister

Jennifer Nichols

Andrea Kranz

A Francis Stewart

Austin Smith

Hendrik G Stunnenberg

Affiliations

Soon will be listed here.

Abstract

Mouse embryonic stem (ES) cells grown in serum exhibit greater heterogeneity in morphology and expression of pluripotency factors than ES cells cultured in defined medium with inhibitors of two kinases (Mek and GSK3), a condition known as "2i" postulated to establish a naive ground state. We show that the transcriptome and epigenome profiles of serum- and 2i-grown ES cells are distinct. 2i-treated cells exhibit lower expression of lineage-affiliated genes, reduced prevalence at promoters of the repressive histone modification H3K27me3, and fewer bivalent domains, which are thought to mark genes poised for either up- or downregulation. Nonetheless, serum- and 2i-grown ES cells have similar differentiation potential. Precocious transcription of developmental genes in 2i is restrained by RNA polymerase II promoter-proximal pausing. These findings suggest that transcriptional potentiation and a permissive chromatin context characterize the ground state and that exit from it may not require a metastable intermediate or multilineage priming.

Citing Articles

AMPK activation by glycogen expenditure primes the exit of naïve pluripotency.

Kim S, Kwon E, Oh J, Kim H, Park S, Jang G EMBO Rep. 2025; .

PMID: 39962227 DOI: 10.1038/s44319-025-00384-x.

X-inactive-specific transcript: a long noncoding RNA with a complex role in sex differences in human disease.

Predescu D, Mokhlesi B, Predescu S Biol Sex Differ. 2024; 15(1):101.

PMID: 39639337 PMC: 11619133. DOI: 10.1186/s13293-024-00681-5.

Long-range regulation of transcription scales with genomic distance in a gene-specific manner.

Jensen C, Chen L, Swigut T, Crocker O, Yao D, Bassik M Mol Cell. 2024; 85(2):347-361.e7.

PMID: 39626660 PMC: 11741922. DOI: 10.1016/j.molcel.2024.10.021.

A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation.

Bertran M, Walmsley R, Cummings T, Aramburu I, Benton D, Mora Molina R Nat Commun. 2024; 15(1):9746.

PMID: 39528459 PMC: 11555231. DOI: 10.1038/s41467-024-53554-1.

DNA methylation shapes the Polycomb landscape during the exit from naive pluripotency.

Richard Albert J, Urli T, Monteagudo-Sanchez A, Le Breton A, Sultanova A, David A Nat Struct Mol Biol. 2024; 32(2):346-357.

PMID: 39448850 DOI: 10.1038/s41594-024-01405-4.

References

Schmitges F, Prusty A, Faty M, Stutzer A, Lingaraju G, Aiwazian J . Histone methylation by PRC2 is inhibited by active chromatin marks. Mol Cell. 2011; 42(3):330-41. DOI: 10.1016/j.molcel.2011.03.025. View

Morris D, Michelotti G, Schwinn D . Evidence that phosphorylation of the RNA polymerase II carboxyl-terminal repeats is similar in yeast and humans. J Biol Chem. 2005; 280(36):31368-77. PMC: 2277102. DOI: 10.1074/jbc.M501546200. View

Hu M, Krause D, Greaves M, Sharkis S, Dexter M, Heyworth C . Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 1997; 11(6):774-85. DOI: 10.1101/gad.11.6.774. View

Penny G, Kay G, Sheardown S, Rastan S, Brockdorff N . Requirement for Xist in X chromosome inactivation. Nature. 1996; 379(6561):131-7. DOI: 10.1038/379131a0. View

Ambrosino C, Tarallo R, Bamundo A, Cuomo D, Franci G, Nassa G . Identification of a hormone-regulated dynamic nuclear actin network associated with estrogen receptor alpha in human breast cancer cell nuclei. Mol Cell Proteomics. 2010; 9(6):1352-67. PMC: 2877992. DOI: 10.1074/mcp.M900519-MCP200. View

Kiyonari H, Kaneko M, Abe S, Aizawa S . Three inhibitors of FGF receptor, ERK, and GSK3 establishes germline-competent embryonic stem cells of C57BL/6N mouse strain with high efficiency and stability. Genesis. 2010; 48(5):317-27. DOI: 10.1002/dvg.20614. View

Takahashi K, Mitsui K, Yamanaka S . Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature. 2003; 423(6939):541-5. DOI: 10.1038/nature01646. View

Li H, Ruan J, Durbin R . Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 2008; 18(11):1851-8. PMC: 2577856. DOI: 10.1101/gr.078212.108. View

Wray J, Kalkan T, Gomez-Lopez S, Eckardt D, Cook A, Kemler R . Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nat Cell Biol. 2011; 13(7):838-45. PMC: 3160487. DOI: 10.1038/ncb2267. View

10.

Min I, Waterfall J, Core L, Munroe R, Schimenti J, Lis J . Regulating RNA polymerase pausing and transcription elongation in embryonic stem cells. Genes Dev. 2011; 25(7):742-54. PMC: 3070936. DOI: 10.1101/gad.2005511. View

11.

Wang W, Yang J, Liu H, Lu D, Chen X, Zenonos Z . Rapid and efficient reprogramming of somatic cells to induced pluripotent stem cells by retinoic acid receptor gamma and liver receptor homolog 1. Proc Natl Acad Sci U S A. 2011; 108(45):18283-8. PMC: 3215025. DOI: 10.1073/pnas.1100893108. View

12.

Smith A . Pluripotent stem cells: private obsession and public expectation. EMBO Mol Med. 2010; 2(4):113-6. PMC: 3377278. DOI: 10.1002/emmm.201000065. View

13.

Fujita T, Ryser S, Piuz I, Schlegel W . Up-regulation of P-TEFb by the MEK1-extracellular signal-regulated kinase signaling pathway contributes to stimulated transcription elongation of immediate early genes in neuroendocrine cells. Mol Cell Biol. 2007; 28(5):1630-43. PMC: 2258797. DOI: 10.1128/MCB.01767-07. View

14.

Boettiger A, Levine M . Synchronous and stochastic patterns of gene activation in the Drosophila embryo. Science. 2009; 325(5939):471-3. PMC: 4280267. DOI: 10.1126/science.1173976. View

15.

Tang F, Barbacioru C, Bao S, Lee C, Nordman E, Wang X . Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-Seq analysis. Cell Stem Cell. 2010; 6(5):468-78. PMC: 2954317. DOI: 10.1016/j.stem.2010.03.015. View

16.

Nichols J, Jones K, Phillips J, Newland S, Roode M, Mansfield W . Validated germline-competent embryonic stem cell lines from nonobese diabetic mice. Nat Med. 2009; 15(7):814-8. DOI: 10.1038/nm.1996. View

17.

Akkers R, van Heeringen S, Jacobi U, Janssen-Megens E, Francoijs K, Stunnenberg H . A hierarchy of H3K4me3 and H3K27me3 acquisition in spatial gene regulation in Xenopus embryos. Dev Cell. 2009; 17(3):425-34. PMC: 2746918. DOI: 10.1016/j.devcel.2009.08.005. View

18.

Rahl P, Lin C, Seila A, Flynn R, McCuine S, Burge C . c-Myc regulates transcriptional pause release. Cell. 2010; 141(3):432-45. PMC: 2864022. DOI: 10.1016/j.cell.2010.03.030. View

19.

Niwa H, Ogawa K, Shimosato D, Adachi K . A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. 2009; 460(7251):118-22. DOI: 10.1038/nature08113. View

20.

Buehr M, Meek S, Blair K, Yang J, Ure J, Silva J . Capture of authentic embryonic stem cells from rat blastocysts. Cell. 2008; 135(7):1287-98. DOI: 10.1016/j.cell.2008.12.007. View