In Huntington disease (HD), the analysis of tissue-specific CAG repeat length effects has been challenging, given the difficulty in obtaining relevant patient tissues with a broad range of CAG repeat lengths. We used genome editing to generate an allelic panel of isogenic HD (IsoHD) human embryonic stem cell (hESC) lines carrying varying CAG repeat lengths in the first exon of HTT. Functional analyses in differentiated neural cells revealed CAG repeat length-related abnormalities in mitochondrial respiration and oxidative stress and enhanced susceptibility to DNA damage. To explore tissue-specific effects in HD, we differentiated the IsoHD panel into neural progenitor cells, neurons, hepatocytes, and muscle cells. Transcriptomic and proteomic analyses of the resultant cell types identified CAG repeat length-dependent and cell-type-specific molecular phenotypes. We anticipate that the IsoHD panel and transcriptomic and proteomic data will serve as a versatile, open-access platform to dissect the molecular factors contributing to HD pathogenesis.
The work was partly funded by a Strategic Positioning Fund for Genetic Orphan Diseases (SPF2012/005) and a Joint Council Office Project grant (1431AFG122) from the Agency for Science, Technology and Research (Singapore) to M.A.P. R.M.S. was supported by Core funding from IMCB and IMB Strategic Positioning Fund (SPF, BMRC, A∗STAR), a Young Investigator Grant ( YIG 2015 ; BMRC, A∗STAR), and an NMRC MS-CETSA platform grant ( MOHIAFCAT2/004/2015 ). A.Z. was supported by the A∗STAR Singapore International Graduate Award ( SINGA ).