The maternally methylated KvDMR1 ICR regulates imprinted expression of a cluster of maternally expressed genes on human chromosome 11p15.5. Disruption of imprinting leads to Beckwith-Wiedemann syndrome (BWS), an overgrowth and cancer predisposition condition. In the majority of individuals with BWS, maternal-specific methylation at KvDMR1 is absent and genes under its control are repressed. We analyzed a mouse model carrying a poly(A) truncation cassette inserted to prevent RNA transcripts from elongation through KvDMR1. Maternal inheritance of this mutation resulted in absence of DNA methylation at KvDMR1, which led to biallelic expression of Kcnq1ot1 and suppression of maternally expressed genes. This study provides further evidence that transcription is required for establishment of methylation at maternal gametic DMRs. More importantly, this mouse model recapitulates the molecular phenotypic characteristics of the most common form of BWS, including loss of methylation at KvDMR1 and biallelic repression of Cdkn1c, suggesting that deficiency of maternal transcription through KvDMR1 may be an underlying cause of some BWS cases.
The authors declare no competing or financial interests.
Conceptualization: V.B.S., M.J.H.; Methodology: V.B.S., S.S., K.E.W., K.M.A., J.C.H., S.P., M.J.H.; Validation: S.S., K.M.A.; Formal analysis: V.B.S., S.S., K.E.W., K.M.A., S.P., M.J.H.; Investigation: M.J.H.; Resources: M.J.H.; Writing - original draft: V.B.S., M.J.H.; Writing - review & editing: V.B.S., S.S., K.M.A., J.C.H., S.P., M.J.H.; Supervision: M.J.H.; Project administration: M.J.H.; Funding acquisition: M.J.H.
This study was supported by National Institutes of Health (NIH) (RO1 CA89426 to M.J.H.) and use core facilities supported in part by the Roswell Park Cancer Institute National Cancer Institute (NCI)-funded Cancer Center Support Grant (P30 CA016056-27). Deposited in PMC for release after 12 months.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.145136.supplemental
- Received September 27, 2016.
- Accepted March 23, 2017.