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

Rustam Esanov, Kinsley C. Belle, Marka van Blitterswijk, Veronique V. Belzil, Rosa 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

10 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

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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