Statistical Enrichment of Epigenetic States Around Triplet Repeats that Can Undergo Expansions

Abstract

More than 30 human genetic diseases are linked to tri-nucleotide repeat expansions. There is no known mechanism that explains repeat expansions in full, but changes in the epigenetic state of the associated locus has been implicated in the disease pathology for a growing number of examples. A comprehensive comparative analysis of the genomic features associated with diverse repeat expansions has been lacking. Here, in an effort to decipher the propensity of repeats to undergo expansion and result in a disease state, we determine the genomic coordinates of tri-nucleotide repeat tracts at base pair resolution and computationally establish epigenetic profiles around them. Using three complementary statistical tests, we reveal that several epigenetic states are enriched around repeats that are associated with disease, even in cells that do not harbor expansion, relative to a carefully stratified background. Analysis of over one hundred cell types reveals that epigenetic states generally tend to vary widely between genic regions and cell types. However, there is qualified consistency in the epigenetic signatures of repeats associated with disease suggesting that changes to the chromatin and the DNA around an expanding repeat locus are likely to be similar. These epigenetic signatures may be exploited further to develop models that could explain the propensity of repeats to undergo expansions.

RNA-Dependent Epigenetic Silencing Directs Transcriptional Downregulation Caused by Intronic Repeat Expansions

“…Epigenetic changes have been implicated in several triplet expansion disorders (Nageshwaran and Festenstein, 2015). It has also been suggested that the repeats that undergo expansion have a distinct association with epigenetic features (Essebier et al, 2016). Our findings reinforce the importance of epigenetic changes in establishing the disease state caused by triplet repeat expansions.…”

Open chromatin structure in PolyQ disease-related genes: a potential mechanism for CAG repeat expansion in the normal human population

“…This characteristic, which is stable across different cell types during early human development, was shown to be disrupted in the FMR1 gene in Fragile X syndrome patients, which correlated with the silencing of that gene. Another study had revealed the absence of repressive marks in CAG expansions related genes ( 20 ). We also provide exemplar density plots for the HM in their genomic coordinates for the polyQ disease-related gene ATXN7 and for another long polyQ-containing gene, which is not disease-associated, FOXP2 ( Supplementary Figure S5 ).…”

“…However, less is known about the causes for repeat expansions that take place in genes that encode for proteins with repeat tracts within the normal range. In healthy cells, DNA methylation and active histone marks were suggested to be enriched around disease-associated TNRs ( 20 ). Interestingly, CAG repeat expansions in bacterial and yeast models, as well as in vitro models using human cell extracts, demonstrated that even short, normal range, repeat tracts are unstable, with a tendency to expand ( 21–23 ).…”