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bioRxiv · 10.1101/2021.09.20.461105

TGS1: a novel regulator of β-cell mass and function

Blandino-Rosano, M.·Romaguera-Llacer, P.·Lin, A.·Reddy, J. K.·Bernal-Mizrachi, E.
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Abstract

Type 2 diabetes (T2D) is a metabolic disorder associated with abnormal glucose homeostasis and is characterized by intrinsic defects in {beta}-cell function and mass. Trimethylguanosine synthase 1 (TGS1) is an evolutionarily conserved enzyme that methylates small nuclear and nucleolar RNAs (snRNAs and snoRNAs) and is involved in pre-mRNA splicing, transcription, and ribosome production. However, the role of TGS1 in {beta}-cells and glucose homeostasis had not been explored. Here we show that TGS1 is upregulated by insulin and upregulated in islets from mice exposed to a high-fat diet and in human {beta}-cells from T2D donors. Using mice with conditional ({beta}TGS1KO and {beta}TGS1Het) and inducible (MIP-CreERT-TGS1KO) TGS1 deletion, we determine that TGS1 regulates {beta}-cell mass and function. Unbiased approaches allowed us to identify a link between TGS1 and ER stress and cell cycle arrest and how TGS1 regulates {beta}-cell apoptosis. Deletion of TGS1 results in an increase in the unfolded protein response by increasing XBP-1, ATF-4, and the phosphorylation of eIF2, and several changes in cell cycle inhibitors and activators such as p27 and Cyclin D2. This study establishes TGS1 as a key player regulating {beta}-cell mass and function as well as playing a role in the adaptive {beta}-cell function to a high-fat diet. These observations can be used as a stepping-stone for the design of novel strategies using TGS1 as a therapeutic target for the treatment of diabetes.

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Blandino-Rosano, M., Romaguera-Llacer, P., Lin, A., Reddy, J. K., Bernal-Mizrachi, E.. 2021-09-20. TGS1: a novel regulator of β-cell mass and function. https://doi.org/10.1101/2021.09.20.461105

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