Distinct Methylation Changes at the IGF2-H19 Locus in Congenital Growth Disorders and Cancer

作者：Adele Murrell, Yoko Itō, Gaetano Verde, Joanna E. Huddleston, Kathryn Woodfine, Margherita Silengo, Filippo Spreafico, Daniela Perotti, Agostina De Crescenzo, Angela Sparago, Flavia Cerrato, Andrea Riccio · 发表于：PLoS ONE · 年份：2008 · DOI：10.1371/journal.pone.0001849 · 被引用次数：104 · 研究领域：Genetic Syndromes and Imprinting、Epigenetics and DNA Methylation、Gestational Trophoblastic Disease Studies

BACKGROUND: Differentially methylated regions (DMRs) are associated with many imprinted genes. In mice methylation at a DMR upstream of the H19 gene known as the Imprint Control region (IC1) is acquired in the male germline and influences the methylation status of DMRs 100 kb away in the adjacent Insulin-like growth factor 2 (Igf2) gene through long-range interactions. In humans, germline-derived or post-zygotically acquired imprinting defects at IC1 are associated with aberrant activation or repression of IGF2, resulting in the congenital growth disorders Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, respectively. In Wilms tumour and colorectal cancer, biallelic expression of IGF2 has been observed in association with loss of methylation at a DMR in IGF2. This DMR, known as DMR0, has been shown to be methylated on the silent maternal IGF2 allele presumably with a role in repression. The effect of IGF2 DMR0 methylation changes in the aetiology of BWS or SRS is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analysed the methylation status of the DMR0 in BWS, SRS and Wilms tumour patients by conventional bisulphite sequencing and pyrosequencing. We show here that, contrary to previous reports, the IGF2 DMR0 is actually methylated on the active paternal allele in peripheral blood and kidney. This is similar to the IC1 methylation status and is inconsistent with the proposed silencing function of the maternal IGF2 allele. Beckwith-Wiedemann and Silver-Russell patients...