Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming

H. Zhang; W. Jiao; L. Sun; J. Fan; M. Chen; H. Wang; X. Xu; A. Shen; T. Li; B. Niu; S. Ge; W. Li; J. Cui; G. Wang; J. Sun; X. Fan; X. Hu; Randy Mrsny; Andrew R. Hoffman; J.-F. Hu

doi:10.1016/j.stem.2013.05.012

Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming

H. Zhang, W. Jiao, L. Sun, J. Fan, M. Chen, H. Wang, X. Xu, A. Shen, T. Li, B. Niu, S. Ge, W. Li, J. Cui, G. Wang, J. Sun, X. Fan, X. Hu, Randy Mrsny, Andrew R. Hoffman, J.-F. Hu

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

114 Citations (SciVal)

Abstract

Generation of induced pluripotent stem cells (iPSCs) by defined factors is an extremely inefficient process, because there is a strong epigenetic block preventing cells from achieving pluripotency. Here we report that virally expressed factors bound to the promoters of their target genes to the same extent in both iPSCs and unreprogrammed cells (URCs). However, expression of endogenous pluripotentcy genes was observed only in iPSCs. Comparison of local chromatin structure of the OCT4 locus revealed that there was a cohesin-complex-mediated intrachromosomal loop that juxtaposes a downstream enhancer to the gene's promoter, enabling activation of endogenous stemness genes. None of these long-range interactions were observed in URCs. Knockdown of the cohesin-complex gene SMC1 by RNAi abolished the intrachromosomal interaction and affected pluripotency. These findings highlight the importance of the SMC1-orchestrated intrachromosomal loop as a critical epigenetic barrier to the induction of pluripotency.

Original language	English
Pages (from-to)	30-35
Number of pages	6
Journal	Cell Stem Cell
Volume	13
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2013.05.012
Publication status	Published - 3 Jul 2013

Funding

This work was supported by the California Institute of Regenerative Medicine (CIRM) (grant RT2-01942), a Jilin International Collaboration Grant (20120720), and an NSFC grant (81272294) to J.F.H; a Jilin Science and Technique Program grant (11GG003) to W.L.; a Merit Review grant from the Medical Research Service of the Department of Veterans Affairs to A.R.H.; an NSFC grant (81172323) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01040411) to S.F.G; and a Shanghai Leading Academic Discipline Project grant (S30205) to X.Q.F. H.Z. is an Early Career Scientist of Shanghai JiaoTong University School of Medicine.

Funders	Funder number
Jilin Science and Technique Program	11GG003
Shanghai Jiao Tong University
U.S. Department of Veterans Affairs	81172323
California Institute for Regenerative Medicine	RT2-01942, 20120720
National Natural Science Foundation of China	81272294
Chinese Academy of Sciences	XDA01040411
Shanghai Leading Academic Discipline Project	S30205

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2013.05.012

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Zhang, H., Jiao, W., Sun, L., Fan, J., Chen, M., Wang, H., Xu, X., Shen, A., Li, T., Niu, B., Ge, S., Li, W., Cui, J., Wang, G., Sun, J., Fan, X., Hu, X., Mrsny, R., Hoffman, A. R., & Hu, J.-F. (2013). Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. Cell Stem Cell, 13(1), 30-35. https://doi.org/10.1016/j.stem.2013.05.012

Zhang, H, Jiao, W, Sun, L, Fan, J, Chen, M, Wang, H, Xu, X, Shen, A, Li, T, Niu, B, Ge, S, Li, W, Cui, J, Wang, G, Sun, J, Fan, X, Hu, X, Mrsny, R, Hoffman, AR & Hu, J-F 2013, 'Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming', Cell Stem Cell, vol. 13, no. 1, pp. 30-35. https://doi.org/10.1016/j.stem.2013.05.012

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abstract = "Generation of induced pluripotent stem cells (iPSCs) by defined factors is an extremely inefficient process, because there is a strong epigenetic block preventing cells from achieving pluripotency. Here we report that virally expressed factors bound to the promoters of their target genes to the same extent in both iPSCs and unreprogrammed cells (URCs). However, expression of endogenous pluripotentcy genes was observed only in iPSCs. Comparison of local chromatin structure of the OCT4 locus revealed that there was a cohesin-complex-mediated intrachromosomal loop that juxtaposes a downstream enhancer to the gene's promoter, enabling activation of endogenous stemness genes. None of these long-range interactions were observed in URCs. Knockdown of the cohesin-complex gene SMC1 by RNAi abolished the intrachromosomal interaction and affected pluripotency. These findings highlight the importance of the SMC1-orchestrated intrachromosomal loop as a critical epigenetic barrier to the induction of pluripotency. ",

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AU - Ge, S.

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AU - Cui, J.

AU - Wang, G.

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AU - Mrsny, Randy

AU - Hoffman, Andrew R.

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Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming

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