Recurrent Variations in DNA Methylation in Human Pluripotent Stem Cells and Their Differentiated Derivatives

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 May 8

PMID 22560082

Citations 217

Authors

Kristopher L Nazor

Gulsah Altun

Candace Lynch

Ha Tran

Julie V Harness

Ileana Slavin

Ibon Garitaonandia

Franz-Josef Muller

Yu-Chieh Wang

Francesca S Boscolo

Eyitayo Fakunle

Biljana Dumevska

Sunray Lee

Hyun Sook Park

Tsaiwei Olee

Darryl D DLima

Ruslan Semechkin

Mana M Parast

Vasiliy Galat

Andrew L Laslett

Uli Schmidt

Hans S Keirstead

Jeanne F Loring

Louise C Laurent

Affiliations

Soon will be listed here.

Abstract

Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting.

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References

Atanasoski S, Notterpek L, Lee H, Castagner F, Young P, Ehrengruber M . The protooncogene Ski controls Schwann cell proliferation and myelination. Neuron. 2004; 43(4):499-511. DOI: 10.1016/j.neuron.2004.08.001. View

Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V . Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391):1145-7. DOI: 10.1126/science.282.5391.1145. View

Nistor G, Totoiu M, Haque N, Carpenter M, Keirstead H . Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia. 2004; 49(3):385-96. DOI: 10.1002/glia.20127. View

Choufani S, Shapiro J, Susiarjo M, Butcher D, Grafodatskaya D, Lou Y . A novel approach identifies new differentially methylated regions (DMRs) associated with imprinted genes. Genome Res. 2011; 21(3):465-76. PMC: 3044860. DOI: 10.1101/gr.111922.110. View

Shen Y, Matsuno Y, Fouse S, Rao N, Root S, Xu R . X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. Proc Natl Acad Sci U S A. 2008; 105(12):4709-14. PMC: 2290804. DOI: 10.1073/pnas.0712018105. View

Aberg K, Saetre P, Jareborg N, Jazin E . Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia. Proc Natl Acad Sci U S A. 2006; 103(19):7482-7. PMC: 1464365. DOI: 10.1073/pnas.0601213103. View

Hough S, Laslett A, Grimmond S, Kolle G, Pera M . A continuum of cell states spans pluripotency and lineage commitment in human embryonic stem cells. PLoS One. 2009; 4(11):e7708. PMC: 2768791. DOI: 10.1371/journal.pone.0007708. View

Allegrucci C, Wu Y, Thurston A, Denning C, Priddle H, Mummery C . Restriction landmark genome scanning identifies culture-induced DNA methylation instability in the human embryonic stem cell epigenome. Hum Mol Genet. 2007; 16(10):1253-68. DOI: 10.1093/hmg/ddm074. View

Pomp O, Dreesen O, Leong D, Meller-Pomp O, Tan T, Zhou F . Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase. Cell Stem Cell. 2011; 9(2):156-65. DOI: 10.1016/j.stem.2011.06.004. View

10.

Teichroeb J, Betts D, Vaziri H . Suppression of the imprinted gene NNAT and X-chromosome gene activation in isogenic human iPS cells. PLoS One. 2011; 6(10):e23436. PMC: 3192059. DOI: 10.1371/journal.pone.0023436. View

11.

McLean C, Bristor D, Hiller M, Clarke S, Schaar B, Lowe C . GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010; 28(5):495-501. PMC: 4840234. DOI: 10.1038/nbt.1630. View

12.

Feng Q, Lu S, Klimanskaya I, Gomes I, Kim D, Chung Y . Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells. 2010; 28(4):704-12. DOI: 10.1002/stem.321. View

13.

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

14.

John R, Lefebvre L . Developmental regulation of somatic imprints. Differentiation. 2011; 81(5):270-80. DOI: 10.1016/j.diff.2011.01.007. View

15.

Uribe-Lewis S, Woodfine K, Stojic L, Murrell A . Molecular mechanisms of genomic imprinting and clinical implications for cancer. Expert Rev Mol Med. 2011; 13:e2. DOI: 10.1017/S1462399410001717. View

16.

Hall L, Byron M, Butler J, Becker K, Nelson A, Amit M . X-inactivation reveals epigenetic anomalies in most hESC but identifies sublines that initiate as expected. J Cell Physiol. 2008; 216(2):445-52. PMC: 3057623. DOI: 10.1002/jcp.21411. View

17.

Ohi Y, Qin H, Hong C, Blouin L, Polo J, Guo T . Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol. 2011; 13(5):541-9. PMC: 3987913. DOI: 10.1038/ncb2239. View

18.

Urbach A, Bar-Nur O, Daley G, Benvenisty N . Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell. 2010; 6(5):407-11. PMC: 3354574. DOI: 10.1016/j.stem.2010.04.005. View

19.

Bhusari S, Yang B, Kueck J, Huang W, Jarrard D . Insulin-like growth factor-2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer. Prostate. 2011; 71(15):1621-30. PMC: 3825178. DOI: 10.1002/pros.21379. View

20.

Muller F, Schuldt B, Williams R, Mason D, Altun G, Papapetrou E . A bioinformatic assay for pluripotency in human cells. Nat Methods. 2011; 8(4):315-7. PMC: 3265323. DOI: 10.1038/nmeth.1580. View