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Weksberg Lab

Domain 1

How do the two domains regulate imprinting on 11p15?

Domain 1 (regulated by DMR1):

Domain 1 contains the genes:

  • Insulin-like growth factor 2 (IGF2) and
  • H19.

A ~0.5kb differentially methylated region, 'DMR1', 2 kb upstream of H19 is postulated to be an imprinting center.

The maternally expressed H19 gene encodes an apparently non-translated RNAPolII transcript that may function as a tumor suppressor. The IGF2 gene encodes a paternally expressed cytokine that plays an important role as a fetal growth factor. Its up-regulation and biological function are thought to play a pivotal role in the pathogenesis of BWS and in a large variety of sporadic tumors.

A.  H19 is normally maternally expressed, IGF2 is normally paternally expressed. H19 is methylated on the paternal allele in the differentially methylated region (DMR1, yellow box) located two kilobases upstream. Methylation may extend all the way down to the H19 promoter region (Methylation is indicated by CH3, yellow CH3 is DMR methylation and promoter methylation is light red). A zinc-finger protein, CTCF "C", binds to the unmethylated DMR1 blocking access of IGF2 to its shared downstream mesodermal and endodermal enhancers (circle with "E").

domain 1 3 part chart

B.  5-10% of BWS patients have a molecular characterization of H19-dependent biallelic IGF2 expression. These patients have hypermethylation, methylation on both the maternal and paternal DMR1. CTCF can no longer bind and IGF2 has access to its downstream enhancers resulting in biallelic expression.

C.  25-50% of BWS patients have H19-independent biallelic IGF2 expression. These patients do not have hypermethylation on the maternal promoter region of H19 and often maintain H19 expression. Binding of CTCF "C" to maternal DMR is not known. Presence of a putative repressor binding sequence "R" in the DMR1 region is inactive when methylated.