Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Cemre Celen; Jen-Chieh Chuang; Shunli Shen; Lin Li; Gianna Maggiore; Yuemeng Jia; Xin Luo; Austin Moore; Yunguan Wang; Jordan E Otto; Clayton K Collings; Zixi Wang; Xuxu Sun; Ibrahim Nassour; Jiyoung Park; Alexandra Ghaben; Tao Wang; Sam C Wang; Philipp E Scherer; Cigall Kadoch; Hao Zhu

doi:10.1016/j.celrep.2022.111581

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Cell Rep. 2022 Nov 1;41(5):111581. doi: 10.1016/j.celrep.2022.111581.

Authors

Cemre Celen¹, Jen-Chieh Chuang¹, Shunli Shen¹, Lin Li¹, Gianna Maggiore¹, Yuemeng Jia¹, Xin Luo¹, Austin Moore¹, Yunguan Wang², Jordan E Otto³, Clayton K Collings³, Zixi Wang¹, Xuxu Sun¹, Ibrahim Nassour⁴, Jiyoung Park⁵, Alexandra Ghaben⁵, Tao Wang⁶, Sam C Wang⁴, Philipp E Scherer⁵, Cigall Kadoch³, Hao Zhu⁷

Affiliations

¹ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Quantitative Biomedical Research Center, Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hao.zhu@utsouthwestern.edu.

PMID: 36323264
DOI: 10.1016/j.celrep.2022.111581

Abstract

The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.

Keywords: Arid1a; CP: Cell biology; CP: Developmental biology; EGFR/ERBB; NR4A nuclear receptors; NRG/EGF signaling; SWI/SNF; chromatin remodeling; diabetes; islets; β-cell regeneration.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Chromatin Assembly and Disassembly
DNA-Binding Proteins / genetics
Epidermal Growth Factor*
Female
Liver Regeneration
Mammals / metabolism
Mice
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
Pregnancy
Signal Transduction
Transcription Factors / genetics

Substances

Epidermal Growth Factor
Nuclear Proteins
Arid1a protein, mouse
DNA-Binding Proteins
Transcription Factors

Grants and funding

R03 ES026397/ES/NIEHS NIH HHS/United States