20 research outputs found

    Insulin-like growth factor 2: Escape from imprinted regulation in the choroid plexus of the mouse

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    EThOS - Electronic Theses Online ServiceGBUnited Kingdo

    Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer

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    Runt domain transcription factor 3 (RUNX3) is widely regarded as a tumour-suppressor gene inactivated by DNA hypermethylation of its canonical CpG (cytidine-phosphate-guanidine) island (CGI) promoter in gastric cancer (GC). Absence of RUNX3 expression from normal gastric epithelial cells (GECs), the progenitors to GC, coupled with frequent RUNX3 overexpression in GC progression, challenge this longstanding paradigm. However, epigenetic models to better describe RUNX3 deregulation in GC have not emerged. Here, we identify lineage-specific DNA methylation at an alternate, non-CGI promoter (P1) as a new mechanism of RUNX3 epigenetic control. In normal GECs, P1 was hypermethylated and repressed, whereas in immune lineages P1 was hypomethylated and widely expressed. In human GC development, we detected aberrant P1 hypomethylation signatures associated with the early inflammatory, preneoplastic and tumour stages. Aberrant P1 hypomethylation was fully recapitulated in mouse models of gastric inflammation and tumorigenesis. Cell sorting showed that P1 hypomethylation reflects altered cell-type composition of the gastric epithelium/tumour microenvironment caused by immune cell recruitment, not methylation loss. Finally, via long-term culture of gastric tumour epithelium, we revealed that de novo methylation of the RUNX3 canonical CGI promoter is a bystander effect of oncogenic immortalization and not likely causal in GC pathogenesis as previously argued. We propose a new model of RUNX3 epigenetic control in cancer, based on immune-specific, non-CGI promoter hypomethylation. This novel epigenetic signature may have utility in early detection of GC and possibly other epithelial cancers with premalignant immune involvement

    WAMIDEX: a web atlas of murine genomic imprinting and differential expression

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    The mouse is an established model organism for the study of genomic imprinting. Mice with genetic material originating from only one parent (e.g., mice with uniparental chromosomal duplications) or gene mutations leading to epigenetic deficiencies have proven to be particularly useful tools. In the process of our studies we have accumulated a large set of expression microarray measurements in samples derived from these types of mice. Here, we present the collation of these and third-party microarray data that are relevant to genomic imprinting into a Web Atlas of Murine genomic Imprinting and Differential EXpression (WAMIDEX: https://atlas.genetics.kcl.ac.uk). WAMIDEX integrates the most comprehensive literature-derived catalog of murine imprinted genes to date with a genome browser that makes the microarray data immediately accessible in annotation-rich genomic context. In addition, WAMIDEX exemplifies the use of the self-organizing map method for the discovery of novel imprinted genes from microarray data. The parent-of-origin-specific expression of imprinted genes is frequently limited to specific tissues or developmental stages, a fact that the atlas reflects in its design and data content

    Genomic imprinting of Dopa decarboxylase in heart and reciprocal allelic expression with neighboring Grb10

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    By combining a tissue-specific microarray screen with mouse uniparental duplications, we have identified a novel imprinted gene, Dopa decarboxylase (Ddc), on chromosome 11. Ddc_exon1a is a 2-kb transcript variant that initiates from an alternative first exon in intron 1 of the canonical Ddc transcript and is paternally expressed in trabecular cardiomyocytes of the embryonic and neonatal heart. Ddc displays tight conserved linkage with the maternally expressed and methylated Grb10 gene, suggesting that these reciprocally imprinted genes may be coordinately regulated. In Dnmt3L mutant embryos that lack maternal germ line methylation imprints, we show that Ddc is overexpressed and Grb10 is silenced. Their imprinting is therefore dependent on maternal germ line methylation, but the mechanism at Ddc does not appear to involve differential methylation of the Ddc exon1a promoter region and may instead be provided by the oocyte mark at Grb10. Our analysis of Ddc redefines the imprinted Grb10 domain on mouse proximal chromosome 11 and identifies Ddc_exon1a as the first example of a heart-specific imprinted gene
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