Epigenetic Alterations Mediate iPSC Normalization of DNA-Repair Expression and TNR Stability in Huntington's Disease
Journal of Cell Science
UNSP jcs215343 (11 pages)
Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat (TNR) expansion within the HTT gene. The mechanisms underlying HD-associated cellular dysfunction in pluripotency and neurodevelopment are poorly understood. We had previously identified downregulation of selected DNA repair genes in HD fibroblasts relative to wild-type fibroblasts, as a result of promoter hypermethylation. Here, we tested the hypothesis that hypomethylation during cellular reprogramming to the induced pluripotent stem cell (iPSC) state leads to upregulation of DNA repair genes and stabilization of TNRs in HD cells. We sought to determine how the HD TNR region is affected by global epigenetic changes through cellular reprogramming and early neurodifferentiation. We find that early stage HD-affected neural stem cells (HD-NSCs) contain increased levels of global 5-hydroxymethylation (5-hmC) and normalized DNA repair gene expression. We confirm TNR stability is induced in iPSCs, and maintained in HD-NSCs. We also identify that upregulation of 5-hmC increases ten-eleven translocation 1 and 2 (TET1/2) protein levels, and show their knockdown leads to a corresponding decrease in the expression of select DNA repair genes. We further confirm decreased expression of TET1/2-regulating miR-29 family members in HD-NSCs. Our findings demonstrate that mechanisms associated with pluripotency induction lead to a recovery in the expression of select DNA repair gene and stabilize pathogenic TNRs in HD.
0000-0002-0621-2819 (Mollica), 0000-0002-9154-1667 (Zamponi), 0000-0003-2989-1292 (Reid), 0000-0003-2844-8790 (White), 0000-0002-4231-9488 (Ogle), 0000-0003-3329-9478 (Bruno), 0000-0002-0871-6789 (Sachs)
Original Publication Citation
Mollica, P. A., Zamponi, M., Reid, J. A., Sharma, D. K., White, A. E., Ogle, R. C., . . . Sachs, P. C. (2018). Epigenetic alterations mediate iPSC normalization of DNA-repair expression and TNR stability in Huntington's disease. Journal of Cell Science 131(13), UNSP jcs215343. doi:10.1242/jcs.215343
Mollica, Peter A.; Zamponi, Martina; Reid, John; Sharma, Deepak; White, Alyson E.; Ogle, Roy C.; Bruno, Robert D.; and Sachs, Patrick C., "Epigenetic Alterations Mediate iPSC Normalization of DNA-Repair Expression and TNR Stability in Huntington's Disease" (2018). Medical Diagnostics & Translational Sciences Faculty Publications. 37.
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Article is open access after a 12-month embargo. © 2018. Published by The Company of Biologists Ltd.