Supervisor name: Erica Watson
sncRNA as a mechanism of transgenerational epigenetic inheritance
Transgenerational epigenetic inheritance (TEI) occurs when an environmental stressor influences epigenetic patterns leading to an increased risk for disease. Remarkably, these pathologies can be inherited by subsequent generations even in the absence of the stressor. The mechanism by which this occurs is not well understood, but excludes changes to the DNA base sequence and is thought to involve epigenetic mechanisms including chromatin modifications and small non-coding RNA (sncRNA). Our research explores the mechanism of TEI in a genetic mouse model of abnormal folate metabolism (Mtrrgt) that displays multigenerational inheritance of developmental phenotypes at least up to the F4 wildtype generation. Folate is a vitamin that is required by one-carbon metabolism for cellular methylation reactions (e.g., methylation of DNA, histones, RNA). Preliminary work in the lab revealed that expression of specific sncRNAs is disrupted in sperm of F0 Mtrr+/gt mice. This occurs in a similar manner to other models of epigenetic inheritance (e.g., paternal high fat/high sugar diet and paternal low protein diet). The proposed project will determine whether dysregulation of sncRNAs in sperm of Mtrr+/gt males is sufficient to cause phenotypes in later development and potentially in the next generation. To do this, synthetic ncRNAs will be injected into wildtype zygotes, which will then be transferred into the uteri of pseudopregnant females. Litters will be assessed at midgestation for developmental phenotypes and compared the Mtrrgt mouse line. Consideration will be given to potential mechanisms. Understanding the epigenetic mechanism of TEI will have implications for preventative medicine and give further sound evidence in support of government programmes of folate-fortification of food, the implementation of which are currently under consideration in the UK. Furthermore, our findings can be applied to the multigenerational effects of other non-communicable diseases, such as diabetes, in hopes of stemming their high prevalence in the UK population.
Relevant references:
1. Padmanabhan et al, 2013. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155(1): 81-93.
2. Watson, 2016. Transferring fragments of paternal metabolism to the offspring. Cell Metabolism 23(3): 401-2.
3. Blake and Watson, 2016. Unravelling the complex mechanisms of transgenerational epigenetic inheritance. Current Opinion of Chemical Biology 33: 101-7.