Epigenetic Memory in Induced Pluripotent Stem Cells

Overview

Journal Nature

Specialty Science

Date 2010 Jul 21

PMID 20644535

Citations 1161

Authors

K Kim

A Doi

B Wen

K Ng

R Zhao

P Cahan

J Kim

M J Aryee

H Ji

L I R Ehrlich

A Yabuuchi

A Takeuchi

K C Cunniff

H Hongguang

S McKinney-Freeman

O Naveiras

T J Yoon

R A Irizarry

N Jung

J Seita

J Hanna

P Murakami

R Jaenisch

R Weissleder

S H Orkin

I L Weissman

A P Feinberg

G Q Daley

Affiliations

Soon will be listed here.

Abstract

Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment.

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References

Pavlidis P, Noble W . Analysis of strain and regional variation in gene expression in mouse brain. Genome Biol. 2001; 2(10):RESEARCH0042. PMC: 57797. DOI: 10.1186/gb-2001-2-10-research0042. View

Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K . Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol. 2009; 27(8):743-5. DOI: 10.1038/nbt.1554. View

Bourne S, Polak J, Hughes S, Buttery L . Osteogenic differentiation of mouse embryonic stem cells: differential gene expression analysis by cDNA microarray and purification of osteoblasts by cadherin-11 magnetically activated cell sorting. Tissue Eng. 2004; 10(5-6):796-806. DOI: 10.1089/1076327041348293. View

Eggan K, Akutsu H, Loring J, Klemm M, Rideout 3rd W, Yanagimachi R . Hybrid vigor, fetal overgrowth, and viability of mice derived by nuclear cloning and tetraploid embryo complementation. Proc Natl Acad Sci U S A. 2001; 98(11):6209-14. PMC: 33447. DOI: 10.1073/pnas.101118898. View

Chan E, Ratanasirintrawoot S, Park I, Manos P, Loh Y, Huo H . Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells. Nat Biotechnol. 2009; 27(11):1033-7. DOI: 10.1038/nbt.1580. View

Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K . Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008; 321(5889):699-702. DOI: 10.1126/science.1154884. View

Ji H, Ehrlich L, Seita J, Murakami P, Doi A, Lindau P . Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature. 2010; 467(7313):338-42. PMC: 2956609. DOI: 10.1038/nature09367. View

Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, Hochedlinger K . A high-efficiency system for the generation and study of human induced pluripotent stem cells. Cell Stem Cell. 2008; 3(3):340-5. PMC: 3987901. DOI: 10.1016/j.stem.2008.08.003. View

Gurdon J, Melton D . Nuclear reprogramming in cells. Science. 2008; 322(5909):1811-5. DOI: 10.1126/science.1160810. View

10.

Markoulaki S, Hanna J, Beard C, Carey B, Cheng A, Lengner C . Transgenic mice with defined combinations of drug-inducible reprogramming factors. Nat Biotechnol. 2009; 27(2):169-71. PMC: 2654270. DOI: 10.1038/nbt.1520. View

11.

Hanna J, Markoulaki S, Schorderet P, Carey B, Beard C, Wernig M . Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell. 2008; 133(2):250-64. PMC: 2615249. DOI: 10.1016/j.cell.2008.03.028. View

12.

Turker M . Gene silencing in mammalian cells and the spread of DNA methylation. Oncogene. 2002; 21(35):5388-93. DOI: 10.1038/sj.onc.1205599. View

13.

Osafune K, Caron L, Borowiak M, Martinez R, Fitz-Gerald C, Sato Y . Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol. 2008; 26(3):313-5. DOI: 10.1038/nbt1383. View

14.

Eden S, Hashimshony T, Keshet I, Cedar H, Thorne A . DNA methylation models histone acetylation. Nature. 1998; 394(6696):842. DOI: 10.1038/29680. View

15.

Zhao X, Li W, Lv Z, Liu L, Tong M, Hai T . iPS cells produce viable mice through tetraploid complementation. Nature. 2009; 461(7260):86-90. DOI: 10.1038/nature08267. View

16.

Chin M, Mason M, Xie W, Volinia S, Singer M, Peterson C . Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell. 2009; 5(1):111-23. PMC: 3448781. DOI: 10.1016/j.stem.2009.06.008. View

17.

Lengerke C, Schmitt S, Bowman T, Jang I, Maouche-Chretien L, McKinney-Freeman S . BMP and Wnt specify hematopoietic fate by activation of the Cdx-Hox pathway. Cell Stem Cell. 2008; 2(1):72-82. DOI: 10.1016/j.stem.2007.10.022. View

18.

Okita K, Ichisaka T, Yamanaka S . Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448(7151):313-7. DOI: 10.1038/nature05934. View

19.

Marion R, Strati K, Li H, Murga M, Blanco R, Ortega S . A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature. 2009; 460(7259):1149-53. PMC: 3624089. DOI: 10.1038/nature08287. View

20.

Wernig M, Lengner C, Hanna J, Lodato M, Steine E, Foreman R . A drug-inducible transgenic system for direct reprogramming of multiple somatic cell types. Nat Biotechnol. 2008; 26(8):916-24. PMC: 2654269. DOI: 10.1038/nbt1483. View