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Mapping the mouse Allelome reveals tissue-specific regulation of allelic expression

ABSTRACT: Allele-specific expression is important in development and disease, but a complete picture is lacking. Therefore, we mapped allelic-specific expression in 23 tissues during mouse development, including 19 female tissues allowing X chromosome inactivation (XCI) escapers to also be detected. By using rRNA depleted RNA-seq we were able to map allelic expression of lncRNAs that may be lowly expressed or non-polyadenylated. Analysis of this data together with ChIP-seq and genetic models reveals previously unappreciated aspects of the regulation of allelic expression. We demonstrate that allelic expression arising from genetic differences between the alleles, or from the epigenetic processes XCI and genomic imprinting, is surprisingly highly tissue-specific. We find that tissue-specific strain-biased gene expression may be regulated by tissue-specific enhancers or by post-transcriptional differences in stability between the alleles. We detect a higher rate of XCI escapers than most previous mouse studies, (∼10% genes escaping per tissue similar to reports in human), while leg muscle shows an unexpectedly high rate of ∼50% escapers. By surveying a range of tissues during development, and by performing extensive validation including an embryo transfer experiment to exclude false positives from placental maternal contamination, we are able to provide a high confidence list of mouse imprinted genes including 18 novel genes. This increases the proportion of imprinted genes that are clustered (>90%), and shows that cluster size varies dynamically during development, and can be substantially larger than previously thought, with the Igf2r cluster extending over 10Mb in placenta, making it the largest autosomal cis-regulated region in mammals.

ORGANISM(S): Mus musculus

PROVIDER: GSE75957 | GEO | 2017/08/22

SECONDARY ACCESSION(S): PRJNA305855

REPOSITORIES: GEO

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Project description:Mammals achieve parity in expression of X linked genes in somatic tissue of males and females through the mechanism of X inactivation. Not all X-linked genes are silenced on the inactivated X, and genes that escape X-inactivation provide key insights about the mechanism of X inactivation. In humans, 15% of X-linked genes escape random X inactivation whereas in mouse 3% of X-linked genes escape inactivation. In marsupials and mouse, extraembryonic tissues (which give rise to the placenta) display another form of dosage compensation called imprinted X inactivation. Imprinted X inactivation is not random, as it is always the paternal X that is inactivated. There are as yet no reports in the literature of genes that might escape imprinted X inactivation. Here, we performed a deep RNA-seq study in mouse placenta samples from reciprocal crosses and discovered that 7.4% (21/282) of X-linked genes escape imprinted X inactivation. Strikingly, there is zero overlap between the set of imprinted X inactivation escapers and random X inactivation escapers. Imprinted X inactivation escapers are stable and show >35% paternal expression compared to >10% expression from the inactive X for random X inactivation escapers. Imprinted X inactivation escapers are all of clear functional importance to the placenta, and they are strongly clustered on the X. GO analysis reveals that glycoproteins and transmembrane proteins are significantly enriched among imprinted X inactivation escapers. The X-added region (XAR) of the eutherian mammal X is autosomal in marsupials and these genes were added to the X in eutherian mammals since the time of common ancestry. Fully 70% of the genes in the XAR escape random X inactivation, as though they have yet to acquire normal dosage compensation. But fewer than 10% of the genes in the X-added region (XAR) escape imprinted X inactivation, consistent with a imprinted X inactivation being a default state, and escape occurs only for genes requiring biallelic expression. The deep interspecific conservation of X inactivation escaper status that we find across mammals (including marsupials) despite the radical variation in mechanism provides strong evidence that there is a functional basis for escaper genes to retain their biallelic expression. Discussion of the specific genes that are escapers of imprinted X inactivation will suggest reasons for this functional conservation.

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Mapping the mouse Allelome reveals tissue-specific regulation of allelic expression

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