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Sökning: WFRF:(Zhang Mingzhi) > (2015-2019) > Transcriptional rea...

Transcriptional reactivation of OTX2, RX1 and SIX3 during reprogramming contributes to the generation of RPE cells from human iPSCs

Li, Peng (författare)
Peking University
Sun, Xiaofeng (författare)
Hunan University of Traditional Chinese Medicine
Ma, Zhizhong (författare)
Peking University
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Liu, Yinan (författare)
Peking University
Jin, Ying (författare)
Peking University
Ge, Ruimin (författare)
Lund University,Lunds universitet,Neural stamcellsbiologi och terapi,Forskargrupper vid Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Neural stem cell biology and therapy,Lund University Research Groups,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Skåne University Hospital
Hao, Limin (författare)
Cellonis Biotechnologies Co.Ltd
Ma, Yanling (författare)
Cellonis Biotechnologies Co.Ltd
Han, Shuo (författare)
Peking University
Sun, Haojie (författare)
Peking University
Zhang, Mingzhi (författare)
Peking University
Li, Ruizhi (författare)
Peking University
Li, Tao (författare)
Zhejiang Normal University
Shen, Li (författare)
Peking University
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 (creator_code:org_t)
Ivyspring International Publisher, 2016
2016
Engelska 13 s.
Ingår i: International Journal of Biological Sciences. - : Ivyspring International Publisher. - 1449-2288. ; 12:5, s. 505-517
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • Directed differentiation of human induced pluripotent stem cells (iPSCs) into retinal pigmented epithelium (RPE) holds great promise in cell replacement therapy for patients suffering from degenerative eye diseases, including age-related macular degeneration (AMD). In this study, we generated iPSCs from human dermal fibroblasts (HDFs) by electroporation with episomal plasmid vectors encoding OCT4, SOX2, KLF4, L-MYC together with p53 suppression. Intriguingly, cell reprogramming resulted in a metastable transcriptional activation and selective demethylation of neural and retinal specification-associated genes, such as OTX2, RX1 and SIX3. In contrast, RPE progenitor genes were transcriptionally silent in HDFs and descendant iPSCs. Overexpression of OCT4 and SOX2 directly stimulated the expression of OTX2, RX1 and SIX3 in HDFs and iPSCs. Luciferase and chromatin immunoprecipitation (ChIP) assays further identified an OCT4- and two SOX2-binding sites located in the proximal promoter of OTX2. Histone acetylation and methylation on the local promoter also participated in the reactivation of OTX2. The transcriptional conversion of RX1 and SIX3 genes partially attributed to DNA demethylation. Subsequently, iPSCs were induced into the RPE cells displaying the characteristics of polygonal shapes and pigments, and expressing typical RPE cell markers. Taken together, our results establish readily efficient and safe protocols to produce iPSCs and iPSC-derived RPE cells, and underline that the reactivation of anterior neural transcription factor OTX2, eye field transcription factor RX1 and SIX3 in iPSCs is a feature of pluripotency acquisition and predetermines the potential of RPE differentiation.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

Epigenetic modification
Induced pluripotent stem cells
Reprogramming
Retinal pigment epithelium

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art (ämneskategori)
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