Genome-wide analysis validates aberrant methylation in fragile X syndrome is specific to the FMR1 locus

• Type of Material: Article
• Authors: Reid S. Alisch, University of Wisconsin–Madison; Tao Wang, Emory University; Pankaj Chopra, Emory University; Jeannie Visootsak, Emory University; Karen N Conneely, Emory University; Stephen Warren, Emory University
• Language: English
• Date: 2013-01-29
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2013 Alisch et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.biomedcentral.com/1471-2350/14/18
• Title of Journal or Parent Work: BMC Medical Genetics
• ISSN: 1471-2350
• Volume: 14
• Issue: 18
• Start Page: 1
• End Page: 7
• Grant/Funding Information: Emory University’s research IT service center and its high performance computer cluster also supported this research.; This work was supported in part by a Simons Foundation (SFARI) award and NIH grants MH089606 and HD24064, all to STW. We are grateful to all the families collected from the Department’s Fragile X Syndrome Clinic and those participating at the SFARI Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, and E. Wijsman). We also appreciate the access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study by applying at https://base.sfari.org. Emory University’s research IT service center and its high performance computer cluster also supported this research.
• Research Categories: Chemistry, Biochemistry; Biology, Molecular; Biology, Genetics

Abstract

Background Fragile X syndrome (FXS) is a common form of inherited intellectual disability caused by an expansion of CGG repeats located in the 5′ untranslated region (UTR) of the FMR1 gene, which leads to hypermethylation and silencing of this locus. Although a dramatic increase in DNA methylation of the FMR1 full mutation allele is well documented, the extent to which these changes affect DNA methylation throughout the rest of the genome has gone unexplored. Methods Here we examined genome-wide methylation in both peripheral blood (N = 62) and induced pluripotent stem cells (iPSCs; N = 10) from FXS individuals and controls. Results We not only found the expected significant DNA methylation differences in the FMR1 promoter and 5′ UTR, we also saw that these changes inverse in the FMR1 gene body. Importantly, we found no other differentially methylated loci throughout the remainder of the genome, indicating the aberrant methylation of FMR1 in FXS is locus-specific. Conclusions This study provides a comprehensive methylation profile of FXS and helps refine our understanding of the mechanisms behind FMR1 silencing.