Epigenetic alterations mediate iPSC-induced normalization of DNA repair gene expression and TNR stability in Huntington's disease cells.

Autor:	Mollica PA; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA.; Molecular Diagnostics Laboratory, Sentara Norfolk General Hospital, Norfolk, VA 23507, USA., Zamponi M; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA.; Biomedical Engineering Institute, Old Dominion University, Norfolk, VA 23529, USA., Reid JA; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA.; Biomedical Engineering Institute, Old Dominion University, Norfolk, VA 23529, USA., Sharma DK; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA., White AE; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA., Ogle RC; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA., Bruno RD; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA psachs@odu.edu rbruno@odu.edu., Sachs PC; Department of Medical Diagnostic and Translational Sciences, Old Dominion University, Norfolk, VA 23529, USA psachs@odu.edu rbruno@odu.edu.
Jazyk:	angličtina
Zdroj:	Journal of cell science [J Cell Sci] 2018 Jul 06; Vol. 131 (13). Date of Electronic Publication: 2018 Jul 06.
DOI:	10.1242/jcs.215343
Abstrakt:	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. Competing Interests: Competing interestsThe authors declare no competing or financial interests. (© 2018. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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