However, a subset of imprinted genes did exhibit associations with placental Cd that may differ among racial subgroups in the RICHS study: CYR61, CDKN1C
, COPG2, and SGCE.
The maternally inherited copy of the IC2 region shows a decrease in the methylation, and this abnormality adversely affects the regulation of several genes that are normally controlled by IC2, including CDKN1C
. Reduction in the activity this gene, which normally controls cell growth and division, leads to overgrowth and the other features of BWS.
The genes encoded at this locus include the genes IGF-R1, CDKN1c
, and non-coding RNAs KCNQ1OT1 and H19.
Interestingly, a specific cluster of mutations in the proliferating cell nuclear antigen-binding domain of the CDKN1C
gene (otherwise shown to cause Beckwith-Wiedemann, an overgrowth syndrome) is responsible for IMAGe syndrome (5).
Nine up-regulated genes CDKN1C
(cyclin-dependent kinase inhibitor 1C), DCN (decorin), HMGN1 (non-histone chromosomal protein HMG-14), HSD17B11 (estradiol 17beta-dehydrogenase 11), LGALS3BP (galectin-3-binding protein), MT2 (metallothionein-2R), RCAN1, SON [a large Ser/Arg (SR)-related protein], and XIST (X-inactive specific transcript) were up-regulated at least 1.5 times, and the RMA conversion value was greater than 0.58.
Expression profile of Cdkn1a and Cdkn1c
mRNA was also analyzed and two distinct profiles were observed.
433 hypermethylated genes were discovered such as Gpr4, Dgcr8, Zeb2, Dixdc1, Sox2, Shh, Lrfn3, Det1, Shox2, Abracl, Trdn, Irx2, Pabpc6, Sbk1, and Peg3.134 hypomethylated genes which included Gpr126, Birc2, Sepw1, Irgq, Atp5sl, Hipk4, Ttc9b, Tulp2, Bex1, Mex3b, Ctsc, Gucy2d, Rrm1, Fam160a2, and Cdkn1c
In vitro studies show induction of imprinted Igf2, Cdkn1c
, H19, Dlk1, and Mest when Zac1 is overexpressed (Varrault et al.