Maternal-Specific Methylation of the HumanIGF2RGene Is Not Accompanied by Allele-Specific Transcription

Abstract

The hum an in su lin -lik e grow th factor type 2 recep tor gen e (IGF2R) is b ia llelica lly expressed in a variety o f fetal and adult tissu es. In contrast, the im printed m ouse Igf2r gen e is exp ressed exclu sively from the ma ternally in h erited chrom osom e. The m ouse gene con tains tw o CpG isla n d s th at are m ethylated in a parentspecific m anner. M éthylation o f th e CpG island in the prom oter region occu rs on th e repressed paternal gene copy. M éthylation of th e CpG island in intron 2 is specific for th e a ctiv e m aternal allele and m ay repre sen t the prim ary im print. H ere, we have analyzed the hum an IGF2R gen e to in v estig a te w hether these m otifs and th eir parent-of-origin-specific epigenetic modifi cation have b een conserved. As in th e mouse, the hu man IGF2R gen e w as found to contain two CpG is lands, one en com p assin g th e transcription start site (CpG 1) and th e oth er in th e second intron (CpG 2). CpG 2 is h yp erm eth ylated on th e m aternal IGF2R al lele. In contrast to th e situ a tio n in th e m ouse, how ever, the hum an CpG 1 is com p letely unm ethylated on both parental chrom osom es, The hum an and m ouse intronic CpG islan d s la ck sign ifican t sequence hom ol ogy* w h ich su g g ests th a t DNA conform ation plays a role in allele-Specific m éthylation.

Multiple imprinted sense and antisense transcripts, differential methylation and tandem repeats in a putative imprinting control region upstream of mouse Igf2

“…Alternatively, imprinting of human IGF2 may occur by a mechanism that does not require a repeat, or may use the variable number tandem repeat at the nearby insulin (INS) locus, different alleles of which influence the magnitude of INS expression (25,26), and might influence IGF2 expression. In any case, the IGF2 gene departs from the situation in the H19 and IGF2R genes, both of which have tandem repeats near DMRs that are associated with germline methylation imprints (5,27).…”

Aberrant imprinting of the insulin-like growth factor II receptor gene in Wilms' tumor

“…Given the evidence of a molecular methylation imprint analogous to that seen in the mouse being present in the human (Smrzka et al, 1995;Riesewijk et al, 1996), a search for IGF2R sequence di erences between imprintor and non-imprintor individuals is underway in our laboratory to answer the questions arising from these observations.…”

Imprinting centers, chromatin structure, and disease

“…The major organizational features of the PWS/AS region and the KIP2/ LIT1 domain resemble those of another intensively studied imprinted region, the Igf2r region in mouse (Fig. 1) [Zwart et al, 2001;Fournier et al, 2002] (in humans, IGF2R and nearby genes are not imprinted in most individuals [Riesewijk et al, 1996]). …”