Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes.
Erica P CaiYuki IshikawaWei ZhangNayara Carvalho LeiteJian LiShurong HouBadr KiafJennifer Hollister-LockNese Kurt YilmazCelia A SchifferDouglas A MeltonStephen M KisslerPeng YiPublished in: Nature metabolism (2020)
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.
Keyphrases
- induced apoptosis
- type diabetes
- cell cycle arrest
- mouse model
- genome wide
- single cell
- cardiovascular disease
- cell therapy
- oxidative stress
- crispr cas
- stem cells
- multiple sclerosis
- signaling pathway
- cell death
- dna methylation
- high throughput
- risk assessment
- emergency department
- cell proliferation
- drug administration
- copy number
- climate change
- adipose tissue
- mesenchymal stem cells
- bone marrow
- skeletal muscle
- adverse drug
- drug induced
- pluripotent stem cells