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

Author

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  • Jianfang Li

    (University of Macau
    the Fifth Affiliated Hospital of Guangzhou Medical University
    Guangzhou Laboratory)

  • Xinwei Wu

    (University of Macau
    Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Jie Ke

    (University of Macau)

  • Minjung Lee

    (Texas A&M University)

  • Qingping Lan

    (University of Macau)

  • Jia Li

    (Texas A&M University
    the First Affiliated Hospital of Guangzhou Medical University)

  • Jianxiu Yu

    (Shanghai Jiao Tong University School of Medicine)

  • Yun Huang

    (Texas A&M University)

  • De-Qiang Sun

    (the Fifth Affiliated Hospital of Guangzhou Medical University
    Zhejiang University School of Medicine)

  • Ruiyu Xie

    (University of Macau
    University of Macau)

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.

Suggested Citation

  • Jianfang Li & Xinwei Wu & Jie Ke & Minjung Lee & Qingping Lan & Jia Li & Jianxiu Yu & Yun Huang & De-Qiang Sun & Ruiyu Xie, 2022. "TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31611-x
    DOI: 10.1038/s41467-022-31611-x
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    References listed on IDEAS

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    Cited by:

    1. Xiaowen Lyu & M. Jordan Rowley & Michael J. Kulik & Stephen Dalton & Victor G. Corces, 2023. "Regulation of CTCF loop formation during pancreatic cell differentiation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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