NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic changes in pluripotency genes. Nuclear reprogramming is an inefficient process and the molecular mechanisms that reset the epigenetic state durin...

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Veröffentlicht in:Stem cells (Dayton, Ohio) Jg. 31; H. 7; S. 1278 - 1286
Hauptverfasser: Luo, Min, Ling, Te, Xie, Wenbing, Sun, He, Zhou, Yonggang, Zhu, Qiaoyun, Shen, Meili, Zong, Le, Lyu, Guoliang, Zhao, Yun, Ye, Tao, Gu, Jun, Tao, Wei, Lu, Zhigang, Grummt, Ingrid
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2013
Oxford University Press
Schlagworte:
Animals
Cell Differentiation - physiology
Cellular Reprogramming - physiology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNA-Binding Proteins - physiology
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
Embryonic Stem Cells - physiology
Epigenetic regulation
Epigenetics
Epigenomics
Gene Expression
Gene Knockdown Techniques
Genes, myc
Induced pluripotent stem cells
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Induced Pluripotent Stem Cells - physiology
Mbd3/NuRD
Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics
Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism
Mi-2 Nucleosome Remodeling and Deacetylase Complex - physiology
Mice
Mice, Inbred CBA
Nanog
Plasmids
Promoter Regions, Genetic
Reprogramming efficiency
SOXB1 Transcription Factors - genetics
Stem cells
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription Factors - physiology
Up-Regulation
Epigenetic regulation
Nanog
Induced pluripotent stem cells
Mbd3/NuRD
Reprogramming efficiency
ISSN:1066-5099, 1549-4918, 1549-4918
Online-Zugang:Volltext
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Zusammenfassung:Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic changes in pluripotency genes. Nuclear reprogramming is an inefficient process and the molecular mechanisms that reset the epigenetic state during iPSC generation are largely unknown. Here, we show that downregulation of the nucleosome remodeling and deacetylation (NuRD) complex is required for efficient reprogramming. Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs by establishing heterochromatic features and silencing embryonic stem cell‐specific marker genes, including Oct4 and Nanog. Depletion of Mbd3, on the other hand, improves reprogramming efficiency and facilitates the formation of pluripotent stem cells that are capable of generating viable chimeric mice, even in the absence of c‐Myc or Sox2. The results establish Mbd3/NuRD as an important epigenetic regulator that restricts the expression of key pluripotency genes, suggesting that drug‐induced downregulation of Mbd3/NuRD may be a powerful means to improve the efficiency and fidelity of reprogramming. STEM Cells2013;31:1278–1286
Bibliographie:Telephone: 86‐755‐26032949; Fax: 86‐755‐26035334
Disclosure of potential conflicts of interest is found at the end of this article.
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March 26, 2013.
Author contributions: Z.L., W.T., and I.G.: conception and design, data analysis and interpretation, writing and approval of manuscript; Z.L., M.L., T.L., H.S., and W.X.: collection and assembly of data, data analysis and interpretation; Y.G.Z.: data analysis and interpretation; Q.Z., M.S., L.Z., and G.L.: collection and assembly of data; Y.Z., T.Y., J.G.: other (support of manuscript); M.L., T.L. W.X., and H.S. contributed equally to this article.
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Telephone: 86‐10‐62767581; Fax: 86‐10‐62751526
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ISSN:1066-5099
1549-4918
1549-4918
DOI:10.1002/stem.1374