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Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation.

Authors
  • Schlüter, Agatha1, 2
  • Sandoval, Juan3
  • Fourcade, Stéphane1, 2
  • Díaz-Lagares, Angel3
  • Ruiz, Montserrat1, 2
  • Casaccia, Patrizia4, 5
  • Esteller, Manel3, 6, 7
  • Pujol, Aurora1, 2, 7
  • 1 Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain. , (Spain)
  • 2 Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain. , (Spain)
  • 3 Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain. , (Spain)
  • 4 Department of Neuroscience and Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • 5 Neuroscience Initiative ASRC CUNY, 85 St Nicholas Terrace, New York, NY 10031.
  • 6 Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Catalonia, Spain. , (Spain)
  • 7 Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain. , (Spain)
Type
Published Article
Journal
Brain Pathology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Nov 01, 2018
Volume
28
Issue
6
Pages
902–919
Identifiers
DOI: 10.1111/bpa.12595
PMID: 29476661
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Epigenomic changes may either cause disease or modulate its expressivity, adding a layer of complexity to mendelian diseases. X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic condition exhibiting discordant phenotypes, ranging from a childhood cerebral inflammatory demyelination (cALD) to an adult-onset mild axonopathy in spinal cords (AMN). The AMN form may occur with superimposed inflammatory brain demyelination (cAMN). All patients harbor loss of function mutations in the ABCD1 peroxisomal transporter of very-long chain fatty acids. The factors that account for the lack of genotype-phenotype correlation, even within the same family, remain largely unknown. To gain insight into this matter, here we compared the genome-wide DNA methylation profiles of morphologically intact frontal white matter areas of children affected by cALD with adult cAMN patients, including male controls in the same age group. We identified a common methylomic signature between the two phenotypes, comprising (i) hypermethylation of genes harboring the H3K27me3 mark at promoter regions, (ii) hypermethylation of genes with major roles in oligodendrocyte differentiation such as MBP, CNP, MOG and PLP1 and (iii) hypomethylation of immune-associated genes such as IFITM1 and CD59. Moreover, we found increased hypermethylation in CpGs of genes involved in oligodendrocyte differentiation, and also in genes with H3K27me3 marks in their promoter regions in cALD compared with cAMN, correlating with transcriptional and translational changes. Further, using a penalized logistic regression model, we identified the combined methylation levels of SPG20, UNC45A and COL9A3 and also, the combined expression levels of ID4 and MYRF to be good markers capable of discriminating childhood from adult inflammatory phenotypes. We thus propose the hypothesis that an epigenetically controlled, altered transcriptional program may drive an impaired oligodendrocyte differentiation and aberrant immune activation in X-ALD patients. These results shed light into disease pathomechanisms and uncover putative biomarkers of interest for prognosis and phenotypic stratification. © 2018 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

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