Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1

Abstract

Genomic imprinting is an epigenetic modification that results in expression from only one of the two parental copies of a gene. Differences in methylation between the two parental chromosomes are often observed at or near imprinted genes. Beckwith-Wiedemann syndrome (BWS), which predisposes to cancer and excessive growth, results from a disruption of imprinted gene expression in chromosome band 11p15.5. One third of individuals with BWS lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene, and it has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS1, 2. Here we show that paternal inheritance of a deletion of KvDMR1 results in the de-repression in cis of six genes, including Cdkn1c, which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20-25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings support the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS.

Genome imprinting regulated by the mouse Polycomb group protein Eed

“…These data indicate that Eed represents an additional mechanism of epigenetic regulation that is required to maintain parent-oforigin expression at specific loci in this cluster. In Eed -/-embryos, Cdkn1c and Ascl2 had LOI but Slc22a1l, Tssc3 and Kcnq1 were properly imprinted, whereas all imprinted genes in the cluster were affected in the KvDMR1/Kcnq1ot1 deletion 19 . Gene-specific LOI was also observed in the cluster of imprinted genes on chromosome 12 (ref.…”

“…5a), as paternal inheritance of a deletion of KvDMR1 results in LOI at these imprinted loci 19 . The observed LOI at these loci may be due to removal of the CpG island at the ICR or to disruption of the Kcnq1ot1 antisense transcript.…”

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

“…This causes growth retardation, which supports the hypothesis that abnormal silencing at CDKN1C and other genes along the domain negatively affects growth. (17) Aberrant imprinting maintenance and growth disorders ICRs carry epigenetic marks that are established in the germ cells and, after fertilisation, are maintained throughout development. Proper establishment, and especially the subsequent somatic maintenance of these marks, is crucial, since their deregulation may lead to complex diseases in humans, and is frequently also observed in cancer.…”

“…Furthermore, in the mouse, deletion of the H19 ICR does not affect the KCNQ1 domain and, conversely, targeting of the KvDMR1 does not alter imprinting at the IGF2-H19 domain. (17,34,35) An emerging question is whether, as opposed to what happens in BWS, increased expression of CDKN1C could be causally involved in SRS. In the novel SRS studies, this was explored by analysis of the KvDMR1, but no methylation changes were detected in the patients analysed.…”

Long non-coding RNA-guided regulation in organisms

“…Kcnq1ot1, a nuclear-retained lncRNA with the length of 91.5 kb, is transcribed by RNAPII from the intron 10 of Kcnq1 gene in an antisense orientation to Kcnq1 [38]. The production of Kcnq1ot1 RNA was first found to be associated with the lineage-specific silencing of dozens of genes within the Kcnq1 locus [38,39]. Recent studies further indicated that the silencing effects are achieved by the interactions of Kcnq1ot1 with chromatin and with the H3K9-and H3K27-specific histone methyltransferases G9a and the polycomb repressive complex 2 (PRC2) [40].…”