PolyQ Disease Related Genes Possess a Permissive Epigenetic Landscape in Embryonic Stem Cells: a Potential Explanation for PolyQ Expansions

The human genome contains dozens of genes which encode for proteins containing long poly-glutamine (polyQ) repeats (usually encoded by CAG codons) of 10Qs or more. However, only nine of these genes have been reported to expand beyond the healthy variation and cause diseases. To address whether these nine disease-associated genes are unique in any way, we compared genetic and epigenetic features and regulation relative to other types of genes, especially CAG-repeat containing genes, which do not cause diseases. Our analyses show that the nine polyQ-disease related genes are characterized by an open chromatin profile, enriched for active chromatin marks and depleted for suppressive chromatin marks, in pluripotent cells. By contrast, genes that encode for polyQ-containing proteins, which are not associated with diseases, or other repeat containing genes possess a suppressive chromatin environment. We propose that this active epigenetic landscape may support decreased stability and susceptibility for expansion mutations.