edchuong.bsky.social
Assistant Professor at the University of Colorado Boulder - Genome regulation, Transposons, Immunity - https://chuonglab.colorado.edu
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I created a brief spreadsheet of reductions I've heard of so far. Any additions you know of (especially if you have the links/receipts) would be great: docs.google.com/spreadsheets...
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Congrats to the team, this is super important for studying TEs!
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Awesome, congrats to the team! 🎉
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Also in this same issue--a fantastic deep dive into the prevalence of transposon exonization by @yarribas.bsky.social !
www.cell.com/cell/fulltex...
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All the credit for this discovery goes to postdoc @giuliapasquesi.bsky.social , who first noticed the isoform in her 2020 Lockdown Sideproject (tm). Her perseverance, creativity, and talent made this study possible and it was an honor to be a part of it. Watch out for her--she's on the job market! 😉
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Beyond IFNAR2, our findings suggest that TE exonization may be a widespread yet hidden source of decoy isoforms that regulate immune signaling.
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Our study shows how TE exonization gave rise to a primate-specific IFN decoy receptor, which acts as a dial to turn down IFN signaling in human cells. While IFN decoy receptors have evolved repeatedly in viruses (eg VACV B18), this is the first host-encoded IFN decoy receptor.
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We also found that risk variants linked to severe COVID-19 in the IFNAR2 locus almost perfectly coincided with splicing QTLs associated with higher relative expression of the decoy. This suggests that variation in IFNAR2 splicing partly underlies individual variation in response to infection.
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Giulia tested this by using CRISPR to dissect out each isoform in human cells, and did a battery of IFN assays. Whenever the short isoform was removed, cells showed more potent IFN responses, including immune gene activation, cytotoxicity, and antiviral effect against DENV-2 & SARS-CoV-2!
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Giulia was surprised to see that the short isoform was ubiquitously expressed, often at >2x levels of the canonical isoform! Expression was conserved in other primates, and the protein was also detectable by mass-spec, suggesting that this isoform evolved an important immune function.
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One caught her eye: a short isoform of the IFN receptor IFNAR2 formed by an exonized Alu. This isoform was first discovered over 20 yrs ago (Pfeffer et al 1997), yet has since been forgotten in the literature, presumably assumed to be silent in human cells.
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Giulia revisited this assumption by digging into public long-read cDNA-seq, looking for exonized TEs that form isoforms with robust expression (>5 TPM) and mass-spec evidence. She uncovered hundreds of isoforms of protein-coding immune genes, which were mostly novel or poorly characterized.
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Most introns are littered with TEs, which can become “exonized” and create cryptic isoform variants. Yet while thousands of exonization events have been detected, only a handful have been studied in detail, with most variants assumed to deleterious or nonfunctional.
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Enter transposable elements (TEs) -- the parasites of the genome! While most TEs are non-coding, they are now appreciated as a source of species-specific regulatory elements, which can drive differences in immune gene regulation. But what about TEs in gene exons?
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Interferon (IFN) signaling is an innate immune pathway important for fighting viruses and diseases like cancer. Variation in IFN activity is strongly linked to differences in disease severity including severe COVID-19. What are the factors that influence IFN variation, within or across species?
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Very cool, I remember reading your work on Staufen-mediated decay and hearing about it from Lynne! No one ever leaves the TE field for long .. looking forward to your eventual return ;)