Control of Imprinting at the Gnas Cluster

Abstract

Genomic imprinting is a form of epigenetic regulation in mammals whereby a small subset of genes is silenced according to parental origin. Early work had indicated regions of the genome that were likely to contain imprinted genes. Distal mouse chromosome 2 is one such region and is associated with devastating but ostensibly opposite phenotypes when exclusively maternally or paternally derived. Misexpression of proteins encoded at the Gnas complex, which is located within the region, can largely account for the imprinting phenotypes. Gnas is a complex locus with extraordinary transcriptional and regulatory complexity. It gives rise to alternatively spliced isoforms that show maternal-, paternal- and biallelic expression as well as a noncoding antisense transcript. The objective of our work at Harwell is to unravel mechanisms controlling the expression of these transcripts. We have performed targeted deletion analysis to test candidate regulatory regions within the Gnas complex and, unlike other imprinted domains, two major control regions have been identified. One controls the imprinted expression of a single transcript and is subsidiary to and must interact with, a principal control region that affects the expression of all transcripts. This principal region contains the promoter for the antisense transcript, expression of which may have a major role in controlling imprinting at the Gnas cluster.