title: Genomic imprinting at a boundary element flanking the SDHD locus.
abstract: Germline mutations in SDHD, a mitochondrial complex II (succinate dehydrogenase) subunit gene at chromosome band 11q23, cause highly penetrant paraganglioma (PGL) tumors when transmitted through fathers. In contrast, maternal transmission rarely, if ever, leads to tumor development. The mechanism underlying this unusual monogenic tumor predisposition pattern is poorly understood. Here, we describe identification of imprinted methylation within an alternative promoter for a large intergenic non-coding RNA located at a distant gene desert boundary flanking SDHD. Methylation at this site primarily occurs within two consecutive HpaII restriction enzyme sites in a tissue-specific manner, most commonly in the adrenal gland. Informative fetal tissues and PGL tumors demonstrate maternal allelic hypermethylation. While a strong binding site for the enhancer-blocking protein CTCF within the alternative promoter shows no evidence of methylation, hyper-methylated adrenal tissues show increased binding of the chromatin-looping factor cohesin relative to the hypo-methylated tissues. These results suggest that the differential allelic methylation we observe at this locus is associated with altered chromatin architectures. These results provide molecular evidence for imprinting at a boundary element flanking the SDHD locus and suggest that epigenetic suppression of the maternal allele is the underlying mechanism of the imprinted penetrance of SDHD mutations.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA. bora.baysal@roswellpark.org
authors.forename: Bora E
authors.initials: BE
authors.lastname: Baysal
authors.forename: Sharen E
authors.initials: SE
authors.lastname: McKay
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Kim
authors.forename: Zimei
authors.initials: Z
authors.lastname: Zhang
authors.forename: Linda
authors.initials: L
authors.lastname: Alila
authors.forename: Joan E
authors.initials: JE
authors.lastname: Willett-Brozick
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Shadel
mesh_terms: D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D019175:DNA Methylation / Q000235:genetics; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D038101:Insulator Elements / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: C491545:SDHD protein, human; D013385:Succinate Dehydrogenase