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The miR-203/ZBTB20/MAFA axis orchestrates pancreatic β-cell maturation and identity during weaning and diabetes

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posted on 2024-07-26, 16:59 authored by Yating Li, Yuqian Yang, Yi Sun, Lu He, Lin Zhao, Haoran Sun, Xiaoai Chang, Rui Liang, Shusen Wang, Xiao Han, Yunxia Zhu

ABSTRACT

Maturation of postnatal β cells is regulated in a cell-autonomous manner, and metabolically stressed β cells regress to an immature state, ensuring defective β-cell function and the onset of type 2 diabetes. The molecular mechanisms connecting the nutritional transition to β-cell maturation remain largely unknown. Here, we report a miR-203/ZBTB20/MAFA regulatory axis that mediates the β-cell maturation process. We show that miR-203 level in β cells changes during the nutritional transition and that miR-203 inhibits β-cell maturation at the neonatal stage and under high-fat diet (HFD) conditions. Using single-cell RNA sequencing, we demonstrated that miR-203 elevation promoted the transition of immature β cells into CgBHi endocrine cells, while suppressing gene expressions associated with β-cell maturation in a ZBTB20/MAFA-dependent manner. ZBTB20 is an authentic target of miR-203 and transcriptionally upregulates MAFA expression. Manipulating the miR-203/ZBTB20/MAFA axis may therefore offer a novel strategy for boosting functional β-cell numbers to alleviate diabetes.



Highlights

Ÿ Nutritional transition from high-fat-rich diet to carbohydrate-rich diet inhibits miR-203 expression.

Ÿ Failure to inhibition of miR-203 during HFD feeding causes β-cell immaturity and loss of identity.

Ÿ Ablation of miR-203 in β cells prevents HFD-induced β-cell dysfunction.

Ÿ The miR-203-ZBTB20-MAFA axis mediates β-cell immaturity and is conserved in humans.

Funding

Education Department of Jiangxi Province > Collaborative Innovation Center for Cardiovascular Disease Translational Medicine

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 82070843 82200919 82270844 82330027

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