Genome-wide characterization of the routes to pluripotency

Samer M.I. Hussein, Mira C. Puri, Peter D. Tonge, Marco Benevento, Andrew J. Corso, Jennifer L. Clancy, Rowland Mosbergen, Mira Li, Dong Sung Lee, Nicole Cloonan, David L.A. Wood, Javier Munoz, Robert Middleton, Othmar Korn, Hardip R. Patel, Carl A. White, Jong Yeon Shin, Maely E. Gauthier, Kim Anh Lê Cao, Jong Il Kim & 12 others Jessica C. Mar, Nika Shakiba, William Ritchie, John E.J. Rasko, Sean M. Grimmond, Peter W. Zandstra, Christine A. Wells, Thomas Preiss, Jeong Sun Seo, Albert J.R. Heck, Ian M. Rogers, Andras Nagy

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and-independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org.

Original languageEnglish
Pages (from-to)198-206
Number of pages9
JournalNature
Volume516
Issue number7530
DOIs
Publication statusPublished - 11 Dec 2014
Externally publishedYes

Keywords

  • induced pluripotent stem cells

Cite this

Hussein, S. M. I., Puri, M. C., Tonge, P. D., Benevento, M., Corso, A. J., Clancy, J. L., ... Nagy, A. (2014). Genome-wide characterization of the routes to pluripotency. Nature, 516(7530), 198-206. https://doi.org/10.1038/nature14046
Hussein, Samer M.I. ; Puri, Mira C. ; Tonge, Peter D. ; Benevento, Marco ; Corso, Andrew J. ; Clancy, Jennifer L. ; Mosbergen, Rowland ; Li, Mira ; Lee, Dong Sung ; Cloonan, Nicole ; Wood, David L.A. ; Munoz, Javier ; Middleton, Robert ; Korn, Othmar ; Patel, Hardip R. ; White, Carl A. ; Shin, Jong Yeon ; Gauthier, Maely E. ; Cao, Kim Anh Lê ; Kim, Jong Il ; Mar, Jessica C. ; Shakiba, Nika ; Ritchie, William ; Rasko, John E.J. ; Grimmond, Sean M. ; Zandstra, Peter W. ; Wells, Christine A. ; Preiss, Thomas ; Seo, Jeong Sun ; Heck, Albert J.R. ; Rogers, Ian M. ; Nagy, Andras. / Genome-wide characterization of the routes to pluripotency. In: Nature. 2014 ; Vol. 516, No. 7530. pp. 198-206.
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Hussein, SMI, Puri, MC, Tonge, PD, Benevento, M, Corso, AJ, Clancy, JL, Mosbergen, R, Li, M, Lee, DS, Cloonan, N, Wood, DLA, Munoz, J, Middleton, R, Korn, O, Patel, HR, White, CA, Shin, JY, Gauthier, ME, Cao, KAL, Kim, JI, Mar, JC, Shakiba, N, Ritchie, W, Rasko, JEJ, Grimmond, SM, Zandstra, PW, Wells, CA, Preiss, T, Seo, JS, Heck, AJR, Rogers, IM & Nagy, A 2014, 'Genome-wide characterization of the routes to pluripotency' Nature, vol. 516, no. 7530, pp. 198-206. https://doi.org/10.1038/nature14046

Genome-wide characterization of the routes to pluripotency. / Hussein, Samer M.I.; Puri, Mira C.; Tonge, Peter D.; Benevento, Marco; Corso, Andrew J.; Clancy, Jennifer L.; Mosbergen, Rowland; Li, Mira; Lee, Dong Sung; Cloonan, Nicole; Wood, David L.A.; Munoz, Javier; Middleton, Robert; Korn, Othmar; Patel, Hardip R.; White, Carl A.; Shin, Jong Yeon; Gauthier, Maely E.; Cao, Kim Anh Lê; Kim, Jong Il; Mar, Jessica C.; Shakiba, Nika; Ritchie, William; Rasko, John E.J.; Grimmond, Sean M.; Zandstra, Peter W.; Wells, Christine A.; Preiss, Thomas; Seo, Jeong Sun; Heck, Albert J.R.; Rogers, Ian M.; Nagy, Andras.

In: Nature, Vol. 516, No. 7530, 11.12.2014, p. 198-206.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hussein, Samer M.I.

AU - Puri, Mira C.

AU - Tonge, Peter D.

AU - Benevento, Marco

AU - Corso, Andrew J.

AU - Clancy, Jennifer L.

AU - Mosbergen, Rowland

AU - Li, Mira

AU - Lee, Dong Sung

AU - Cloonan, Nicole

AU - Wood, David L.A.

AU - Munoz, Javier

AU - Middleton, Robert

AU - Korn, Othmar

AU - Patel, Hardip R.

AU - White, Carl A.

AU - Shin, Jong Yeon

AU - Gauthier, Maely E.

AU - Cao, Kim Anh Lê

AU - Kim, Jong Il

AU - Mar, Jessica C.

AU - Shakiba, Nika

AU - Ritchie, William

AU - Rasko, John E.J.

AU - Grimmond, Sean M.

AU - Zandstra, Peter W.

AU - Wells, Christine A.

AU - Preiss, Thomas

AU - Seo, Jeong Sun

AU - Heck, Albert J.R.

AU - Rogers, Ian M.

AU - Nagy, Andras

PY - 2014/12/11

Y1 - 2014/12/11

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Hussein SMI, Puri MC, Tonge PD, Benevento M, Corso AJ, Clancy JL et al. Genome-wide characterization of the routes to pluripotency. Nature. 2014 Dec 11;516(7530):198-206. https://doi.org/10.1038/nature14046