New perspectives on imprinting disease

Project: Research council

Project Details

Description

Mammalian cells typically have two sets of chromosomes, one each inherited from the mother and the father. In most cases, both parental genes (alleles) have similar activities, but in an important minority (~0.5% of the total), the allele inherited from one parent is active relative to the corresponding allele from the other. These genes are said to be imprinted, and the balance of their expression is critical for embryonic viability and the avoidance of disease.

The chromatin marks that engender imprinted gene expression can take the comparatively stable form of genomic DNA methylation and have been known for some thirty years. Recently, it has been found that histones, which package genomic DNA, also carry imprints that seem only to last during preimplantation development; after this, expression from each parental allele becomes equivalent.

We recently documented both imprint types in the mouse by combining parent-discriminatory single embryo genome methylation and gene expression analyses. This work confirmed well-characterised imprints, but suggested that there exist multiple new imprinted regions that had not previously been reported, including 71 new imprinted genes called nBiX (for novel blastocyst-imprinted expressed). Mouse nBiX genes were marked by the modified histone (trimethylation of lysine 27 in histone 3, H3K27me3) and uniparentally expressed at the blastocyst stage before implantation, but equivalently expressed shortly thereafter: they are transiently imprinted.

nBiX genes are highly expressed in the developing brain and almost all have human counterparts that are associated with disease: many are involved in metabolic and membrane regulation, so their dysregulation manifests in diverse pathologies. Disruption of known imprinted genes is oncogenic, linking imprinted gene regulation and cancer, and there is increasing evidence that epigenetic dysregulation in early embryos results in adult disease: examples include nuclear transfer cloning (which produces obesity and other pathologies) and inter-generational epigenetic inheritance, in which parentally-acquired disease traits become heritable.

The present proposal seeks to test the unscrutinised hypothesis that transient disruption of imprinted (particularly nBiX) gene expression during the preimplantation window of uniparental expression causes disease. We will determine at high resolution which traits are dysregulated when nBiX expression levels are briefly disrupted during preimplantation development. This will be accomplished using embryological tools developed by us to increase or reduce nBiX transcript activity at specified stages in mouse preimplantation development.

From preliminary analysis, such transient disruption of nBiX expression impedes embryogenesis. We will extend this to a fuller analysis of the pathological consequences of nBiX disruption using molecular, cellular and physiological approaches, as it manifests at all stages pre- and post-implantation, peri-natal development and into adulthood. The mouse studies will be informed by in-depth analysis of parent-specific genome activity in human blastocysts, allowing us to map mouse nBiX dysregulation in disease onto human imprints.

There is currently no alternative experimental strategy to the one proposed reversibly to abrogate transient imprinted gene expression and reveal links to disease. The imprinting phenomenon is transient and subtle: H3K27me3 may be displaced long before disease is manifest, requiring new perspectives to study it. The work promises to reveal epigenetically-regulated mechanisms predisposing to cancer, and to establish a new and tractable embryonic model. More broadly it will show how the earliest events in embryonic development can effect epigenetic inheritance of disease traits, informing ART so that it may be adapted to minimise epigenetic contributions that predispose to disease.
StatusActive
Effective start/end date17/07/2216/01/26

Funding

  • MRC

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

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