Gender Differences in Global but Not Targeted Demethylation in IPSC Reprogramming

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2017 Feb 2

PMID 28147265

Citations 30

Authors

Ines Milagre

Thomas M Stubbs

Michelle R King

Julia Spindel

Fatima Santos

Felix Krueger

Martin Bachman

Anne Segonds-Pichon

Shankar Balasubramanian

Simon R Andrews

Wendy Dean

Wolf Reik

Affiliations

Soon will be listed here.

Abstract

Global DNA demethylation is an integral part of reprogramming processes in vivo and in vitro, but whether it occurs in the derivation of induced pluripotent stem cells (iPSCs) is not known. Here, we show that iPSC reprogramming involves both global and targeted demethylation, which are separable mechanistically and by their biological outcomes. Cells at intermediate-late stages of reprogramming undergo transient genome-wide demethylation, which is more pronounced in female cells. Global demethylation requires activation-induced cytidine deaminase (AID)-mediated downregulation of UHRF1 protein, and abolishing demethylation leaves thousands of hypermethylated regions in the iPSC genome. Independently of AID and global demethylation, regulatory regions, particularly ESC enhancers and super-enhancers, are specifically targeted for hypomethylation in association with transcription of the pluripotency network. Our results show that global and targeted DNA demethylation are conserved and distinct reprogramming processes, presumably because of their respective roles in epigenetic memory erasure and in the establishment of cell identity.

Citing Articles

The influence of sex-specific factors on biological transformations and health outcomes in aging processes.

Huang Y, Li H, Liang R, Chen J, Tang Q Biogerontology. 2024; 25(5):775-791.

PMID: 39001953 PMC: 11374838. DOI: 10.1007/s10522-024-10121-x.

A disease-specific iPS cell resource for studying rare and intractable diseases.

Saito M, Osawa M, Tsuchida N, Shiraishi K, Niwa A, Woltjen K Inflamm Regen. 2023; 43(1):43.

PMID: 37684663 PMC: 10485998. DOI: 10.1186/s41232-023-00294-2.

Compromised Mitotic Fidelity in Human Pluripotent Stem Cells.

Milagre I, Pereira C, Oliveira R Int J Mol Sci. 2023; 24(15).

PMID: 37569309 PMC: 10418648. DOI: 10.3390/ijms241511933.

Connecting the mechanisms of tumor sex differences with cancer therapy.

Li H, Jiang W, Liu S, Yang M, Chen S, Pan Y Mol Cell Biochem. 2023; 479(2):213-231.

PMID: 37027097 DOI: 10.1007/s11010-023-04723-1.

Harshening stem cell research and precision medicine: The states of human pluripotent cells stem cell repository diversity, and racial and sex differences in transcriptomes.

Nguyen T, Lac Q, Abdi L, Banerjee D, Deng Y, Zhang Y Front Cell Dev Biol. 2023; 10:1071243.

PMID: 36684445 PMC: 9848738. DOI: 10.3389/fcell.2022.1071243.

References

Chen J, Liu H, Liu J, Qi J, Wei B, Yang J . H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat Genet. 2012; 45(1):34-42. DOI: 10.1038/ng.2491. View

Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K . In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature. 2007; 448(7151):318-24. DOI: 10.1038/nature05944. 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

Doege C, Inoue K, Yamashita T, Rhee D, Travis S, Fujita R . Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature. 2012; 488(7413):652-5. PMC: 5176099. DOI: 10.1038/nature11333. View

Stadler M, Murr R, Burger L, Ivanek R, Lienert F, Scholer A . DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011; 480(7378):490-5. DOI: 10.1038/nature10716. View

Sun J, Keim C, Wang J, Kazadi D, Oliver P, Rabadan R . E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells. Genes Dev. 2013; 27(16):1821-33. PMC: 3759698. DOI: 10.1101/gad.210211.112. View

Yoshida Y, Takahashi K, Okita K, Ichisaka T, Yamanaka S . Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell. 2009; 5(3):237-41. DOI: 10.1016/j.stem.2009.08.001. View

Hon G, Song C, Du T, Jin F, Selvaraj S, Lee A . 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol Cell. 2014; 56(2):286-297. PMC: 4319980. DOI: 10.1016/j.molcel.2014.08.026. 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

10.

Sridharan R, Tchieu J, Mason M, Yachechko R, Kuoy E, Horvath S . Role of the murine reprogramming factors in the induction of pluripotency. Cell. 2009; 136(2):364-77. PMC: 3273494. DOI: 10.1016/j.cell.2009.01.001. View

11.

Hu X, Zhang L, Mao S, Li Z, Chen J, Zhang R . Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell Stem Cell. 2014; 14(4):512-22. DOI: 10.1016/j.stem.2014.01.001. View

12.

von Meyenn F, Reik W . Forget the Parents: Epigenetic Reprogramming in Human Germ Cells. Cell. 2015; 161(6):1248-51. DOI: 10.1016/j.cell.2015.05.039. View

13.

Lee D, Shin J, Tonge P, Puri M, Lee S, Park H . An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator. Nat Commun. 2014; 5:5619. PMC: 4284806. DOI: 10.1038/ncomms6619. View

14.

Soufi A, Donahue G, Zaret K . Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell. 2012; 151(5):994-1004. PMC: 3508134. DOI: 10.1016/j.cell.2012.09.045. View

15.

Mikkelsen T, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P . Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008; 454(7200):49-55. PMC: 2754827. DOI: 10.1038/nature07056. View

16.

Seisenberger S, Andrews S, Krueger F, Arand J, Walter J, Santos F . The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell. 2012; 48(6):849-62. PMC: 3533687. DOI: 10.1016/j.molcel.2012.11.001. View

17.

Shirane K, Kurimoto K, Yabuta Y, Yamaji M, Satoh J, Ito S . Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells. Dev Cell. 2016; 39(1):87-103. DOI: 10.1016/j.devcel.2016.08.008. View

18.

Chen H, Ma H, Inuzuka H, Diao J, Lan F, Shi Y . DNA damage regulates UHRF1 stability via the SCF(β-TrCP) E3 ligase. Mol Cell Biol. 2013; 33(6):1139-48. PMC: 3592027. DOI: 10.1128/MCB.01191-12. View

19.

Tchieu J, Kuoy E, Chin M, Trinh H, Patterson M, Sherman S . Female human iPSCs retain an inactive X chromosome. Cell Stem Cell. 2010; 7(3):329-42. PMC: 2935700. DOI: 10.1016/j.stem.2010.06.024. View

20.

Wiench M, John S, Baek S, Johnson T, Sung M, Escobar T . DNA methylation status predicts cell type-specific enhancer activity. EMBO J. 2011; 30(15):3028-39. PMC: 3160184. DOI: 10.1038/emboj.2011.210. View