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Cambridge Reproduction SRI

 

The mechanism and function of non-canonical imprinting during development

Imprinting is a phenomenon whereby certain genes are expressed preferentially from one allele in a parent-of-origin specific manner and is essential for mammalian development. Most genes subject to imprinting are associated with differentially DNA methylated regions dependent on de novo DNA methylation in gametes. However conceptuses derived from oocytes with specific knock-outs of de novo DNA methyltransferases have no loss of imprinting for a subset of genes in extra-embryonic lineages and thus these genes are non-canonically imprinted (NCI). NCI genes are universally proximal to ERVK LTR elements in the genome that are also subject to placental specific imprinted expression.  Analysis of publically available datasets and whole genome bisulphite sequencing of cultured hybrid mouse trophoblast stem cells (TSCs) reveal this system recapitulates the imprinted expression and chromatin state of NCI genes post-implantation. Furthermore, knock-out of an NCI ERVK LTR element within the Gab1 locus causes complete abolition of the imprinted expression of this gene.

Future work will focus on the  molecular and phenotypic characterisation of NCI ERVK LTR knock-outs in both TSCs and mice. This will establish whether all NCI LTRs are required for NCI gene expression,  the essential “readers” of the LTR signal that lead to NCI imprinting and determine the impact of disruption of NCI on reproduction and development.