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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Vydané v:	Stem cells (Dayton, Ohio) Ročník 31; číslo 7; s. 1278 - 1286
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2013 Oxford University Press
Predmet:	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
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Abstract	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
AbstractList	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 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. 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 [PUBLICATION ABSTRACT] 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.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.
Author	Luo, Min Tao, Wei Ling, Te Zong, Le Zhao, Yun Shen, Meili Xie, Wenbing Lu, Zhigang Zhou, Yonggang Lyu, Guoliang Sun, He Grummt, Ingrid Zhu, Qiaoyun Gu, Jun Ye, Tao
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Keywords	Epigenetic regulation Nanog Induced pluripotent stem cells Mbd3/NuRD Reprogramming efficiency
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Notes	Telephone: 86‐755‐26032949; Fax: 86‐755‐26035334 Disclosure of potential conflicts of interest is found at the end of this article. C XPRESS E 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. first published online in S Telephone: 86‐10‐62767581; Fax: 86‐10‐62751526 TEM ELLS ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
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Snippet	Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic...
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SubjectTerms	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
Title	NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells
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