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Analysis of epigenetic and genomic stability in model of abnormal folate metabolism

Analysis of epigenetic and genomic stability in model of abnormal folate metabolism

 

Co-Supervisors: Dr Erica Watson and Dr Russell Hamilton

Dept: Physiology, Development and Neuroscience

Contact: edw23@cam.ac.uk

Environmental stressors (e.g., nutritional deficiency) that we are exposed to in our lifetime may lead to increased disease risk in our children and grandchildren even when they are not exposed to the same stressor. While not well understood, the underlying mechanism might be independent of the DNA base sequence and is expected to occur through the inheritance of an unknown epigenetic factor. However, how the underlying DNA sequence influences epigenetic inheritance has not been properly explored. To understand this phenomenon, we study a mouse model whereby the gene Mtrr, encoding a key enzyme in the folate cycle, is mutated (Mtrrgt). Folate metabolism is required for DNA synthesis and cellular methylation (e.g., DNA and RNA methylation). Mtrr deficiency results in abnormal folate metabolism and epigenetic instability (e.g., DNA hyper- and hypomethylation), and the transgenerational inheritance of a wide spectrum of congenital malformations (e.g., neural tube, heart, placenta defects) in their genetically wildtype grandprogeny and great grandprogeny. The lab aims to identify the inherited epigenetic factor(s) that cause the transgenerational epigenetic inheritance (TEI) of phenotypes in this model and potential genetic instability that may exacerbate the effect.

This project will use new Nanopore sequencing technology to assess the repetitive genome of the Mtrrgt model of TEI. Nanopore sequencing involves passing native DNA or RNA molecules through protein pores resulting in an electrical signal characteristic of each base. The Nanopore is also able to distinguish between nucleotide modifications including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) without chemical or enzymatic treatments, such as with bisulfite sequencing. The lengths of the molecules are typically between 5Kb to 1Mb, which allows for unique mapping over repetitive regions, thus opening up uncharacterized genomic regions. The main aims of the project are:

1. To perform a detailed assessment of the Mtrr gene region, which contains a gene-trap insertion and a different genetic background from the remaining genome.

2. To explore DNA methylation and sequence in repeat regions of the Mtrrgt model over multiple generations, and relate the findings to specific congenital malformations (e.g., placental phenotypes).

Relevant references:

  1. Padmanabhan N, et al., 2013. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155(1): 81-93.
  2. Elmore CL, et al., 2007. Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase. Mol Genet Metab 90(5): 85-97.
  3. Blake GET, Watson ED. 2016. Unravelling the complex mechanisms of transgenerational epigenetic inheritance. Current Opinion in Chemical Biology 33: 101-7.
  4. Prater, M. & Hamilton, R.S. 2018 Epigenetics: Analysis of cytosine modifications at single base resolution. Encyclopedia of Bioinformatics and Computational Biology 3: 341-353