FIGURE 5.

Well-studied imprinting clusters and their conditions in disorder conditions involved in human imprinting disturbance-related diseases. (A,B) BWS and two related imprinted clusters, H19/IGF2 and KCNQ1OT1. (A) The first situation is the hypomethylation of the maternal allele in Kcnq1ot1 ICR leads to lncRNA KCNQ1OT1 overexpression. The expression of neighboring imprinted genes, such as SLC22A18, CDKN1C, and TSSC4, is bi-allelically silenced. (B) The second major imprinting disorder responsible for BWS is hypermethylation of the maternal ICR, resulting in loss of H19 expression and IGF2 overexpression. (C) SRS and alterations in imprinting of H19/IGF2 locus. Hypomethylation of the paternal H19/IGF2 ICR resulting in H19 overexpression and inhibited Igf2 expression. (D) The regulation of mouse Meg3 imprinted cluster. On the paternal allele, the gDMR of Meg3 cluster ICR is methylated, repressing Meg3 lncRNA expression. On the maternal allele, lncRNAs are transcribed from the promoter within the unmethylated ICR. (E) Four cases of MEG3-related imprinting disorders in KOS14 patients are shown. Line I, epimutations in normally activated maternal ICR of MEG3 cluster result in loss of lncRNA transcription, releasing normally silenced adjacent imprinted genes; Line II: maternal deletion in ICR of MEG3 regions; Line III: maternal deletion in the MEG3 gene body; Line IV: both alleles are inherited by silenced paternal allele.