Title

Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Schiffer Lab

Publication Date

2020-07-27

Document Type

Article

Disciplines

Biochemistry, Biophysics, and Structural Biology | Endocrine System Diseases | Endocrinology | Genetics and Genomics | Immune System Diseases | Immunology and Infectious Disease | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Nutritional and Metabolic Diseases

Abstract

Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, thus raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells. Using a genome-scale CRISPR screen in a mouse model for T1D, we show that deleting RNLS, a genome-wide association study candidate gene for T1D, made beta cells resistant to autoimmune killing. Structure-based modelling identified the U.S. Food and Drug Administration-approved drug pargyline as a potential RNLS inhibitor. Oral pargyline treatment protected transplanted beta cells in diabetic mice, thus leading to disease reversal. Furthermore, pargyline prevented or delayed diabetes onset in several mouse models for T1D. Our results identify RNLS as a modifier of beta cell vulnerability and as a potential therapeutic target to avert beta cell loss in T1D.

Keywords

Autoimmunity, pancreatic beta cells, Type 1 diabetes, CRISPR

DOI of Published Version

10.1038/s42255-020-0254-1

Source

Cai EP, Ishikawa Y, Zhang W, Leite NC, Li J, Hou S, Kiaf B, Hollister-Lock J, Yilmaz NK, Schiffer CA, Melton DA, Kissler S, Yi P. Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes. Nat Metab. 2020 Jul 27. doi: 10.1038/s42255-020-0254-1. Epub ahead of print. PMID: 32719542. Link to article on publisher's site

Journal/Book/Conference Title

Nature metabolism

Related Resources

Link to Article in PubMed

PubMed ID

32719542

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