Journal Article

Epigenetic Variation Illustrated by DNA Methylation Patterns of the Fragile-X Gene <i>FMR1</i>

Reinhard Stöger, Tina M. Kajimura, W. Ted Brown and Charles D. Laird

in Human Molecular Genetics

Volume 6, issue 11, pages 1791-1801
Published in print October 1997 | ISSN: 0964-6906
Published online October 1997 | e-ISSN: 1460-2083 | DOI:
Epigenetic Variation Illustrated by DNA Methylation Patterns of the Fragile-X Gene FMR1

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Genomic methylation patterns of mammals can vary among individuals and are subject to dynamic changes during development. In order to gain a better understanding of this variation, we have analyzed patterns of cytosine methylation within a 200 bp region at the CpG island of the human FMR1 gene from leukocyte DNA. FMR1 is normally methylated during inactivation of the X chromosome in females and it is also methylated and inactivated upon expansion of CGG repeats in fragile-X syndrome. Patterns of methylation (epigenotypes) were determined by the sequencing of bisulfite-treated alleles from normal males and females and alleles from a family of five brothers who are methylation mosaics and are affected to various degrees by the fragile-X syndrome. Our data indicate that: (i) methylation of individual CpG cytosines is strikingly variable in hypermethylated epigenotypes obtained from a single individual, suggesting that maintenance of cytosine methylation is a dynamic process; (ii) methylation of non-CpG cytosines in the region studied may occur but is rare; (iii) mosaicism of methylation in the analyzed fragile-X males is remarkably similar to that found for the active X and inactive X alleles in normal females, suggesting that the methylation mosaicism of some fragile-X males reflects similar on and off states of FMR1 expression that exist in normal females; (iv) hypermethylation is slightly more pronounced on fragile-X alleles than on normal inactive X alleles of females; (v) the general dichotomy of hypo- and hypermethylated alleles persisted over the 5 year period that separated samplings of the fragile-X males; (vi) methylation variability was most pronounced at a consensus binding sequence for the α-PAL transcription factor, a sequence that may play a role in regulating expression of FMR1.

Journal Article.  8867 words.  Illustrated.

Subjects: Genetics and Genomics

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