Unbiased Profiling of Isogenic Huntington Disease hPSC-Derived CNS and Peripheral Cells Reveals Strong Cell-Type Specificity of CAG Length Effects

• DOI: 10.1016/j.celrep.2019.02.008
• Publication Date: 2019-02-26T15:42:07Z
• Authors: Jolene Ooi; Sarah R. Langley; Xiaohong Xu; Kagistia H. Utami; Bernice Sim; Yihui Huang; Nathan P. Harmston; Yi Lin Tay; Amin Ziaei; Ruizhu Zeng; Donovan Low; Folefac Aminkeng; Radoslaw M. Sobota; Florent Ginhoux; Enrico Petretto; Mahmoud A. Pouladi
• Keywords: Cell type

In Huntington disease (HD), the analysis of tissue-specific CAG repeat length effects has been challenging, given difficulty in obtaining relevant patient tissues with a broad range lengths. We used genome editing to generate an allelic panel isogenic HD (IsoHD) human embryonic stem cell (hESC) lines carrying varying lengths first exon HTT. Functional analyses differentiated neural cells revealed length-related abnormalities mitochondrial respiration and oxidative stress enhanced susceptibility DNA damage. To explore HD, we IsoHD into progenitor cells, neurons, hepatocytes, muscle cells. Transcriptomic proteomic resultant types identified length-dependent cell-type-specific molecular phenotypes. anticipate that transcriptomic data will serve as versatile, open-access platform dissect factors contributing pathogenesis.