A hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Zhou, Ting; Kim, Tae; Chong, Chi; Tan, Lei; Amin, Sadaf; Sadat Badieyan, Zohreh; Mukherjee, Suranjit; Ghazizadeh, Zaniar; Zeng, Hui; Guo, Min; Crespo, Miguel; Zhang, Tuo; Kenyon, Reyn; Robinson, Christopher; Apostolou, Effie; Wang, Hui; Xiang, Jenny; Evans, Todd; Studer, Lorenz; Chen, Shuibing
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 13
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-07201-1
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract Common disorders, including diabetes and Parkinson's disease, are caused by a combination of environmental factors and genetic susceptibility. However, defining the mechanisms underlying gene-environment interactions has been challenging due to the lack of a suitable experimental platform. Using pancreatic β-like cells derived from human pluripotent stem cells (hPSCs), we discovered that a commonly used pesticide, propargite, induces pancreatic β-cell death, a pathological hallmark of diabetes. Screening a panel of diverse hPSC-derived cell types we extended this observation to a similar susceptibility in midbrain dopamine neurons, a cell type affected in Parkinson's disease. We assessed gene-environment interactions using isogenic hPSC lines for genetic variants associated with diabetes and Parkinson's disease. We foundGSTT1 −/− pancreatic β-like cells and dopamine neurons were both hypersensitive to propargite-induced cell death. Our study identifies an environmental chemical that contributes to human β-cell and dopamine neuron loss and validates a novel hPSC-based platform for determining gene-environment interactions. Diseases such as diabetes and Parkinson's manifest based on interactions between genes and environment. Here, the authors find among a panel of cell types that propargite, a common pesticide, induces pancreatic β-cell and dopamine neuron death and that loss of the gene GSTT1 confers hypersensitivity.