Science with Angela

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Week 8 

Hello my fellow abstract watchers! This week I'm trying to stick to my goal of an abstract a day, not 7 a week compressed into one day. I'm also trying to let myself off the hook and lower my expectations so that this gets done - so I'm just going to read them or spend 15 mins at most on them. Otherwise this task becomes, embarrasingly, too onerous. But I don't want to give up entirely, because just reading and staying on top of recent discoveries has been great.

So - here we go ;)



Abstract 49 Recurrent repeat expansions in human cancer genomes open access, preprint available about 4 months earlier. 

Take-home: Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases, particularly neurological and neurodegenerative disorders. Some cancers are known to have microsatellite instability: mutations accumulate in short tracts of TRs. Whether larger repeat expansions occur in cancer is not known. The authors looked at 2,622 cancer genomes spanning 29 cancer types and found 160 recurrent repeat expansions (rREs) in 7 cancer types. rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, 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. UGT2B7 encodes a glucuronidase that clears small molecules from the body and is selectively expressed in the kidney and liver. Treating cells that harbour this rRE with a GAAA-targeting molecule* led to a dose-dependent decrease in cell proliferation


* First of all - these expansions appear to reduce expression of the "host" gene. Second, in 2017 this lab demonstrated "Synthetic transcription elongation factors license transcription across repressive chromatin" Specifically, they reported Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich’s ataxia, a terminal neurodegenerative disease with no effective therapy. At that time, it was suggested that similar interventions may be effective in a other diseases caused by unstable expansions in microsatellite repeats - and the Nature paper above does just that.


"The woods are lovely, dark and deep"

Robert Frost