The overall objective of our research program is
to define genomic targets that couple maternal nutrition
during pregnancy to adult susceptibility to cancer
and behavioral disorders, such as autism, bipolar
disease and schizophrenia. Both monoallelically expressed
imprinted genes, and transposable elements adjacent
to mammalian genes are genomic targets that can link
nutritional perturbations in methylation during early
development directly to the etiology of adult pathologies.
Consistent with this postulate, we have shown that
maternal dietary methyl donor supplementation (i.e.
folic acid, vitamin B12, choline and betaine) of Agouti
mice during pregnancy alters adult phenotype by methylating
a transposon in the promoter of the Agouti gene, not
by directly mutating the gene. This epigenetic change
not only changes coat color of offspring but also
reduces their susceptibility to obesity, diabetes,
and cancer; a clear example of "Nature via Nurture".
We are also presently utilizing phylogenetic comparisons
of orthologous sequences from members of the three
extant mammalian orders, Prototheria, Metatheria and
Eutheria to characterize the evolution of imprinted
domain structures. The fundamental cis-acting imprint
regulatory elements that epigenetically delineate
the parental alleles constitute the targets for epigenetic
dysregulation. Thus, the successful completion of
these comparative phylogenetic studies will significantly
enhance our understanding of the evolution of this
unique mammalian form of gene regulation. They will
also assist us in characterizing the less well-defined
imprinted domains predicted to harbor genetic and/or
epigenetic mutations mechanistically involved in cancer,
schizophrenia, bipolar disease and autism.
