ARID1A loss in pancreas leads to islet developmental defect and metabolic disturbance

Tzu-Lei Kuo; Kuang-Hung Cheng; Li-Tzong Chen; Wen-Chun Hung

doi:10.1016/j.isci.2022.105881

ARID1A loss in pancreas leads to islet developmental defect and metabolic disturbance

iScience. 2022 Dec 27;26(1):105881. doi: 10.1016/j.isci.2022.105881. eCollection 2023 Jan 20.

Authors

Tzu-Lei Kuo¹, Kuang-Hung Cheng², Li-Tzong Chen^{1

3

4}, Wen-Chun Hung^{1

5

4}

Affiliations

¹ National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
² Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
³ Division of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁴ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
⁵ School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Abstract

ARID1A is a tumor suppressor gene mutated in 7-10% of pancreatic cancer patients. However, its function in pancreas development and endocrine regulation is unclear. We generated mice that lack Arid1a expression in the pancreas. Our results showed that deletion of the Arid1a gene in mice caused a reduction in islet numbers and insulin production, both of which are associated with diabetes mellitus (DM) phenotype. RNA sequencing of isolated islets confirmed DM gene signature and decrease of developmental lineage genes. We identified neurogenin3, a transcription factor that controls endocrine fate specification, is a direct target of Aird1a. Gene set enrichment analysis indicated the enhancement of histone deacetylase (HDAC) pathway after Arid1a depletion and a clinically approved HDAC inhibitor showed therapeutic benefit by suppressing disease onset. Our data suggest that Arid1a is required for the development of pancreatic islets by regulating Ngn3⁺-mediated transcriptional program and is important in maintaining endocrine function.

Keywords: Diabetology; Endocrine regulation; Endocrinology; Omics; Transcriptomics.