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TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
Li, Jianfang1,2,3; Wu, Xinwei1,8; Ke, Jie1; Lee, Minjung4; Lan, Qingping1; Li, Jia4,9; Yu, Jianxiu5; Huang, Yun4; Sun, De Qiang2,6; Xie, Ruiyu1,7
2022-07-07
Source PublicationNature Communications
Volume13Issue:1
Abstract

Existing knowledge of the role of epigenetic modifiers in pancreas development has exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine specification remains obscure. We set out to tackle this issue using a human embryonic stem cell (hESC) differentiation system, in which TET1/TET2/TET3 triple knockout cells display severe defects in pancreatic β-cell specification. The integrative whole-genome analysis identifies unique cell-type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and remarkable enrichment of FOXA2, a pioneer transcription factor essential for pancreatic endoderm specification. Intriguingly, TET depletion leads to significant changes in FOXA2 binding at the pancreatic progenitor stage, in which gene loci with decreased FOXA2 binding feature low levels of active chromatin modifications and enriches for bHLH motifs. Transduction of full-length TET1 but not the TET1-catalytic-domain in TET-deficient cells effectively rescues β-cell differentiation accompanied by restoring PAX4 hypomethylation. Taking these findings together with the defective generation of functional β-cells upon TET1-inactivation, our study unveils an essential role of TET1-dependent demethylation in establishing β-cell identity. Moreover, we discover a physical interaction between TET1 and FOXA2 in endodermal lineage intermediates, which provides a mechanistic clue regarding the complex crosstalk between TET dioxygenases and pioneer transcription factors in epigenetic regulation during pancreas specification.

DOI10.1038/s41467-022-31611-x
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000825808100007
Scopus ID2-s2.0-85133647992
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Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorSun, De Qiang; Xie, Ruiyu
Affiliation1.Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, 999078, Macao
2.Innovation Center for Advanced Interdisciplinary Medicine, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510530, China
3.Guangzhou Laboratory, Guangzhou, 510005, China
4.Center for Epigenetics & Disease Prevention, Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, 77030, United States
5.Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
6.Cardiology Department, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
7.Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, 999078, Macao
8.Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, United States
9.State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences;  University of Macau
Recommended Citation
GB/T 7714
Li, Jianfang,Wu, Xinwei,Ke, Jie,et al. TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation[J]. Nature Communications,2022,13(1).
APA Li, Jianfang,Wu, Xinwei,Ke, Jie,Lee, Minjung,Lan, Qingping,Li, Jia,Yu, Jianxiu,Huang, Yun,Sun, De Qiang,&Xie, Ruiyu.(2022).TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation.Nature Communications,13(1).
MLA Li, Jianfang,et al."TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation".Nature Communications 13.1(2022).
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