Erwin, A. A. | Search bioRxiv

bioRxiv2022

A genome-wide atlas of recurrent repeat expansions in human cancer

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs (STRs), a phenomenon termed microsatellite instability (MSI); however larger repeat expansions have not been systematically analyzed in cancer. Here, we identified TR expansions in 2,622 cancer genomes, spanning 29 cancer types. In 7 cancer types, we found 160 recurrent repeat expansions (rREs); most of these (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with an enrichment near candidate cis-regulatory elements, suggesting a role in gene regulation. One rRE located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, targeting cells harboring this rRE with a rationally designed, sequence-specific DNA binder led to a dose-dependent decrease in cell proliferation. Overall, our results demonstrate that rREs are an important but unexplored source of genetic variation in human cancers, and we provide a comprehensive catalog for further study.

genomics↗

bioRxiv2018

Contrasting effects of aging on the expression of transposons, the piRNA machinery and mitochondrial transcripts in the Drosophila ovary.

Redistribution of heterochromatin during aging has been linked to the de-repression of transposable elements and an overall loss of gene regulation in the soma. Whether or not epigenetic factors such as heterochromatin marks are perturbed in reproductive and germline tissues is of particular interest because some epigenetic factors are known to transmit across generations. Additionally, the relative contribution of factors intrinsic or extrinsic to the germ line have in reproductive decline remains unknown. Using mRNA sequencing data from late stage egg chambers in Drosophila melanogaster, we show that age-related expression changes occur in genes residing in heterochromatin, particularly on the largely heterochromatic 4th chromosome. In addition, we identify an increase in expression of the piRNA machinery. We further identify a striking age-related reduction in mitochondrial transcripts that we can attribute to the somatic tissues. Other than a modest increase in overall TE expression in the aging germline, we find no global TE de-repression in reproductive tissues. Rather, the observed effects of aging on TEs are primarily strain and family specific. These results indicate unique responses in somatic versus germline tissue with regards to epigenetic aging effects and suggest that the global loss of TE control observed in other studies may be specific to certain tissues, genetic backgrounds and TE family. This study also demonstrates that while age-related effects can be maternally transmitted, the germline is generally robust to age-related changes.

evolutionary biology↗