C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells

Rustam Esanov, Kinsley C. Belle, Marka Van Blitterswijk, Veronique Belzil, Rosa V Rademakers, Dennis W Dickson, Leonard Petrucelli, Kevin B. Boylan, Derek M. Dykxhoorn, Joanne Wuu, Michael Benatar, Claes Wahlestedt, Zane Zeier

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Among several genetic mutations known to cause amyotrophic lateral sclerosis (ALS), a hexanucleotide repeat expansion in the C9orf72 gene is the most common. In approximately 30% of C9orf72-ALS cases, 5-methylcytosine (5mC) levels within the C9orf72 promoter are increased, resulting in a modestly attenuated phenotype. The developmental timing of C9orf72 promoter hypermethylation and the reason why it occurs in only a subset of patients remain unknown. In order to model the acquisition of C9orf72 hypermethylation and examine the potential role of 5-hydroxymethylcytosine (5hmC), we generated induced pluripotent stem cells (iPSCs) from an ALS patient with C9orf72 promoter hypermethylation. Our data show that 5mC levels are reduced by reprogramming and then re-acquired upon neuronal specification, while 5hmC levels increase following reprogramming and are highest in iPSCs and motor neurons. We confirmed the presence of 5hmC within the C9orf72 promoter in post-mortem brain tissues of hypermethylated patients. These findings show that iPSCs are a valuable model system for examining epigenetic perturbations caused by the C9orf72 mutation and reveal a potential role for cytosine demethylation.

Original languageEnglish (US)
Pages (from-to)171-177
Number of pages7
JournalExperimental Neurology
Volume277
DOIs
StatePublished - Mar 1 2016

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Keywords

  • Amyotrophic lateral sclerosis
  • C9orf72
  • Cytosine hydroxymethylation
  • Repeat expansion

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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