SUMMARY
As much as 50% of primate genomes are comprised of transposable elements (TEs). While these elements
were originally thought to be junk DNA, newer technologies and approaches have provided insight into how TEs
can contribute to molecular and organismal phenotypes. Given their current or previous ability to move within
host genomes, TEs have the potential to exert both beneficial and deleterious effects on the organism by
contributing gene regulatory sequence. Indeed, TEs can generate gene regulatory innovation leading to
evolutionary novelty and adaptation, while TE mis-regulation associates with various diseases including cancer.
Despite the prevalence of TEs we understand relatively little about how millions of these elements in the human
genome contribute to genome function and expression. Our overarching hypothesis is that TEs exert their gene
regulatory effects in specific environmental contexts. To begin to dissect human TE regulation, this proposal will
make use of evolutionary functional genomics approaches in a cell culture model derived from human individuals
and our closest evolutionary relatives the chimpanzee. In support of our hypothesis, our previous work, together
with that of many others, has indicated that TEs can indeed be regulated through chromatin modifications, DNA
methylation and transcription factor binding. We have also shown that gene expression is dynamic in response
to the environment within and between species, which supports the role of the non-coding genome in mediating
phenotypic effects through gene regulation. We have taken advantage of a flexible induced pluripotent stem cell
(iPSC) based system to generate cell types that can be carefully perturbed, allowing for gene regulatory and
cellular responses to be determined and correlated. In this proposal we will use iPSC technology applied to a
panel of human and chimpanzee individuals, together with functional genomics and cellular assays to dissect
the role of transposable elements in mediating phenotypic effects. First, we will investigate TE regulatory
dynamics during lineage commitment by asking: 1) How do TEs contribute to cell type specification in primates?
and 2) How do TEs contribute to germ layer specification in primates? Second, we will investigate the evolution
of TE regulatory dynamics in response to cellular stress by asking 3) How do stress responses evolve in
primates? and 4) Do TEs contribute to stress responses in primates? Our research will result in an understanding
of the potential for TEs to act as regulatory sequence in the genome that may only be revealed in particular cell
states, or in response to perturbation. This may ultimately provide insight into how aberrant regulation of, and by
TEs can contribute to disease states.