H3K9 Tri-methylation at Nanog Times Differentiation Commitment and Enables the Acquisition of Primitive Endoderm Fate

Overview

Journal Development

Specialty Biology

Date 2022 Aug 17

PMID 35976266

Authors

Agnes Dubois

Loris Vincenti

Almira Chervova

Maxim V C Greenberg

Sandrine Vandormael-Pournin

Deborah Bourchis

Michel Cohen-Tannoudji

Pablo Navarro

Affiliations

Soon will be listed here.

Abstract

Mouse embryonic stem cells have an inherent propensity to explore gene regulatory states associated with either self-renewal or differentiation. This property depends on ERK, which downregulates pluripotency genes such as Nanog. Here, we aimed at identifying repressive histone modifications that would mark Nanog for inactivation in response to ERK activity. We found that the transcription factor ZFP57, which binds methylated DNA to nucleate heterochromatin, is recruited upstream of Nanog, within a region enriched for histone H3 lysine 9 tri-methylation (H3K9me3). Whereas before differentiation H3K9me3 at Nanog depends on ERK, in somatic cells it becomes independent of ERK. Moreover, the loss of H3K9me3 at Nanog, induced by deleting the region or by knocking out DNA methyltransferases or Zfp57, is associated with reduced heterogeneity of NANOG, delayed commitment into differentiation and impaired ability to acquire a primitive endoderm fate. Hence, a network axis centred on DNA methylation, ZFP57 and H3K9me3 links Nanog regulation to ERK activity for the timely establishment of new cell identities. We suggest that establishment of irreversible H3K9me3 at specific master regulators allows the acquisition of particular cell fates during differentiation.

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References

Grabole N, Tischler J, Hackett J, Kim S, Tang F, Leitch H . Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation. EMBO Rep. 2013; 14(7):629-37. PMC: 3701237. DOI: 10.1038/embor.2013.67. View

Illingworth R, Holzenspies J, Roske F, Bickmore W, Brickman J . Polycomb enables primitive endoderm lineage priming in embryonic stem cells. Elife. 2016; 5. PMC: 5056788. DOI: 10.7554/eLife.14926. View

Jenuwein T, Allis C . Translating the histone code. Science. 2001; 293(5532):1074-80. DOI: 10.1126/science.1063127. View

Schroter C, Rue P, Mackenzie J, Martinez Arias A . FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells. Development. 2015; 142(24):4205-16. PMC: 4689219. DOI: 10.1242/dev.127530. View

Artus J, Panthier J, Hadjantonakis A . A role for PDGF signaling in expansion of the extra-embryonic endoderm lineage of the mouse blastocyst. Development. 2010; 137(20):3361-72. PMC: 2947752. DOI: 10.1242/dev.050864. View

Chazaud C, Yamanaka Y, Pawson T, Rossant J . Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell. 2006; 10(5):615-24. DOI: 10.1016/j.devcel.2006.02.020. View

Bernard L, Dubois A, Heurtier V, Fischer V, Gonzalez I, Chervova A . OCT4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 Lysine 9 methylation to pluripotency. Nucleic Acids Res. 2022; 50(13):7367-7379. PMC: 9303268. DOI: 10.1093/nar/gkac550. View

Nichols J, Silva J, Roode M, Smith A . Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development. 2009; 136(19):3215-22. PMC: 2739140. DOI: 10.1242/dev.038893. View

Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K . The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003; 113(5):631-42. DOI: 10.1016/s0092-8674(03)00393-3. View

10.

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

11.

Navarro P, Festuccia N, Colby D, Gagliardi A, Mullin N, Zhang W . OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells. EMBO J. 2012; 31(24):4547-62. PMC: 3545296. DOI: 10.1038/emboj.2012.321. View

12.

Martello G, Smith A . The nature of embryonic stem cells. Annu Rev Cell Dev Biol. 2014; 30:647-75. DOI: 10.1146/annurev-cellbio-100913-013116. View

13.

Singh A, Hamazaki T, Hankowski K, Terada N . A heterogeneous expression pattern for Nanog in embryonic stem cells. Stem Cells. 2007; 25(10):2534-42. DOI: 10.1634/stemcells.2007-0126. View

14.

Bessonnard S, Coqueran S, Vandormael-Pournin S, Dufour A, Artus J, Cohen-Tannoudji M . ICM conversion to epiblast by FGF/ERK inhibition is limited in time and requires transcription and protein degradation. Sci Rep. 2017; 7(1):12285. PMC: 5612930. DOI: 10.1038/s41598-017-12120-0. View

15.

Abranches E, Guedes A, Moravec M, Maamar H, Svoboda P, Raj A . Stochastic NANOG fluctuations allow mouse embryonic stem cells to explore pluripotency. Development. 2014; 141(14):2770-9. PMC: 6517831. DOI: 10.1242/dev.108910. View

16.

Festuccia N, Gonzalez I, Navarro P . The Epigenetic Paradox of Pluripotent ES Cells. J Mol Biol. 2016; 429(10):1476-1503. DOI: 10.1016/j.jmb.2016.12.009. View

17.

Hastreiter S, Skylaki S, Loeffler D, Reimann A, Hilsenbeck O, Hoppe P . Inductive and Selective Effects of GSK3 and MEK Inhibition on Nanog Heterogeneity in Embryonic Stem Cells. Stem Cell Reports. 2018; 11(1):58-69. PMC: 6066909. DOI: 10.1016/j.stemcr.2018.04.019. View

18.

Anderson K, Hamilton W, Roske F, Azad A, Knudsen T, Canham M . Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm. Nat Cell Biol. 2017; 19(10):1164-1177. DOI: 10.1038/ncb3617. View

19.

Balazsi G, van Oudenaarden A, Collins J . Cellular decision making and biological noise: from microbes to mammals. Cell. 2011; 144(6):910-25. PMC: 3068611. DOI: 10.1016/j.cell.2011.01.030. View

20.

Martinez Arias A, Brickman J . Gene expression heterogeneities in embryonic stem cell populations: origin and function. Curr Opin Cell Biol. 2011; 23(6):650-6. DOI: 10.1016/j.ceb.2011.09.007. View