Using hESCs to Probe the Interaction of the Diabetes-Associated Genes CDKAL1 and MT1E.

Summary Genome-wide association studies (GWASs) have identified many disease-associated variant alleles, but understanding whether and how different genes/loci interact requires a platform for probing how the variant alleles act mechanistically. Isogenic mutant human embryonic stem cells (hESCs) provide an unlimited resource to derive and study human disease-relevant cells. Here, we focused on CDKAL1 , linked by GWASs to diabetes. Through transcript profiling, we find that expression of the metallothionein ( MT ) gene family, also linked by GWASs to diabetes, is significantly downregulated in CDKAL1 −/− cells that have been differentiated to insulin-expressing pancreatic beta-like cells. Forced MT1E expression rescues both hypersensitivity of CDKAL1 mutant cells to glycolipotoxicity and pancreatic beta-cell dysfunction in vitro and in vivo. MT1E functions at least in part through relief of ER stress. This study establishes an isogenic hESC-based platform to study the interaction of GWAS-identified diabetes gene variants and illuminate the molecular network impacting disease progression. [ABSTRACT FROM AUTHOR]