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TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation

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...

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Autores principales: Li, Jianfang, Wu, Xinwei, Ke, Jie, Lee, Minjung, Lan, Qingping, Li, Jia, Yu, Jianxiu, Huang, Yun, Sun, De-Qiang, Xie, Ruiyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263144/
https://www.ncbi.nlm.nih.gov/pubmed/35798741
http://dx.doi.org/10.1038/s41467-022-31611-x
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author Li, Jianfang
Wu, Xinwei
Ke, Jie
Lee, Minjung
Lan, Qingping
Li, Jia
Yu, Jianxiu
Huang, Yun
Sun, De-Qiang
Xie, Ruiyu
author_facet Li, Jianfang
Wu, Xinwei
Ke, Jie
Lee, Minjung
Lan, Qingping
Li, Jia
Yu, Jianxiu
Huang, Yun
Sun, De-Qiang
Xie, Ruiyu
author_sort Li, Jianfang
collection PubMed
description 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.
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spelling pubmed-92631442022-07-09 TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation Li, Jianfang Wu, Xinwei Ke, Jie Lee, Minjung Lan, Qingping Li, Jia Yu, Jianxiu Huang, Yun Sun, De-Qiang Xie, Ruiyu Nat Commun Article 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. Nature Publishing Group UK 2022-07-07 /pmc/articles/PMC9263144/ /pubmed/35798741 http://dx.doi.org/10.1038/s41467-022-31611-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Li, Jianfang
Wu, Xinwei
Ke, Jie
Lee, Minjung
Lan, Qingping
Li, Jia
Yu, Jianxiu
Huang, Yun
Sun, De-Qiang
Xie, Ruiyu
TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
title TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
title_full TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
title_fullStr TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
title_full_unstemmed TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
title_short TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
title_sort tet1 dioxygenase is required for foxa2-associated chromatin remodeling in pancreatic beta-cell differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263144/
https://www.ncbi.nlm.nih.gov/pubmed/35798741
http://dx.doi.org/10.1038/s41467-022-31611-x
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