Josh Mendell
@mendell-lab.bsky.social
Scientist in Dept of Mol Bio, UTSW/HHMI, studying post-transcriptional regulation & noncoding RNAs. Opinions are my own and do not reflect those of my employer.
https://labs.utsouthwestern.edu/mendell-lab
https://www.hhmi.org/scientists/joshua-t-mendell
https://labs.utsouthwestern.edu/mendell-lab
https://www.hhmi.org/scientists/joshua-t-mendell
And check out related work from the Bartel lab (@bartellab.bsky.social) 👇
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
mRNA 3′ UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth
MicroRNAs direct downregulation of target mRNAs. Sometimes, however, this regulatory paradigm inverts, and a target RNA triggers the degradation of a microRNA. This target-directed microRNA degradatio...
www.biorxiv.org
November 11, 2025 at 1:24 PM
And check out related work from the Bartel lab (@bartellab.bsky.social) 👇
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
Thank you Davide!
October 17, 2025 at 6:41 PM
Thank you Davide!
Thank you Jinfan!
October 15, 2025 at 9:22 PM
Thank you Jinfan!
Thank you Julius!
October 15, 2025 at 1:58 PM
Thank you Julius!
I would also like to thank Claire Lundstrom and He Zhang (not on Bluesky) for their critical contributions to this work.
October 14, 2025 at 10:28 PM
I would also like to thank Claire Lundstrom and He Zhang (not on Bluesky) for their critical contributions to this work.
Altogether, these findings demonstrate how ‘programmed’ ribosome collisions enable the selective regulation of gene expression and reveal a new mechanism by which the translation machinery senses and responds to stress in order to maintain homeostasis.
October 14, 2025 at 10:28 PM
Altogether, these findings demonstrate how ‘programmed’ ribosome collisions enable the selective regulation of gene expression and reveal a new mechanism by which the translation machinery senses and responds to stress in order to maintain homeostasis.
Beyond selenoprotein-encoding transcripts, ribosome collisions occur at defined sites throughout the transcriptome, pointing to broader control of translation by EEF1G-mediated redox sensing.
October 14, 2025 at 10:28 PM
Beyond selenoprotein-encoding transcripts, ribosome collisions occur at defined sites throughout the transcriptome, pointing to broader control of translation by EEF1G-mediated redox sensing.
Excitingly, Fred identified the elongation factor EEF1G as a key redox sensor that directly slows the rate of translation elongation in response to oxidative stress to decrease ribosome collisions and thereby enhance detoxifying selenoprotein production.
October 14, 2025 at 10:28 PM
Excitingly, Fred identified the elongation factor EEF1G as a key redox sensor that directly slows the rate of translation elongation in response to oxidative stress to decrease ribosome collisions and thereby enhance detoxifying selenoprotein production.
Using genome-wide CRISPR screens, Fred unexpectedly discovered that the production of selenoproteins is limited by ribosome collisions that occur at inefficiently decoded Sec codons.
October 14, 2025 at 10:28 PM
Using genome-wide CRISPR screens, Fred unexpectedly discovered that the production of selenoproteins is limited by ribosome collisions that occur at inefficiently decoded Sec codons.
Fred began this study by investigating how cells regulate the incorporation of the non-canonical amino acid selenocysteine (Sec) into polypeptides. Sec is inserted during translation at recoded UGA termination codons and plays a vital role in metazoan redox biology.
October 14, 2025 at 10:28 PM
Fred began this study by investigating how cells regulate the incorporation of the non-canonical amino acid selenocysteine (Sec) into polypeptides. Sec is inserted during translation at recoded UGA termination codons and plays a vital role in metazoan redox biology.
Altogether, this study provides a valuable dataset that will facilitate identification of additional mammalian TDMD triggers and establishes the existence of a Plagl1/Lrrc58-mediated TDMD pathway that plays a major role in regulating mammalian body size. /end
July 2, 2025 at 4:17 PM
Altogether, this study provides a valuable dataset that will facilitate identification of additional mammalian TDMD triggers and establishes the existence of a Plagl1/Lrrc58-mediated TDMD pathway that plays a major role in regulating mammalian body size. /end
Interestingly, Plagl1 encodes a transcription factor that promotes embryonic growth by transactivating Igf2 expression. This function likely synergizes with the noncoding function of this mRNA in removing the growth suppressing miRNA miR-322 through TDMD.
July 2, 2025 at 4:17 PM
Interestingly, Plagl1 encodes a transcription factor that promotes embryonic growth by transactivating Igf2 expression. This function likely synergizes with the noncoding function of this mRNA in removing the growth suppressing miRNA miR-322 through TDMD.
We further demonstrate that deletion of the trigger sites in the 3' UTRs of these mRNAs in mice results in miR-322/503-dependent embryonic growth restriction, thereby recapitulating a key aspect of the ZSWIM8-deficiency phenotype.
July 2, 2025 at 4:17 PM
We further demonstrate that deletion of the trigger sites in the 3' UTRs of these mRNAs in mice results in miR-322/503-dependent embryonic growth restriction, thereby recapitulating a key aspect of the ZSWIM8-deficiency phenotype.
But the presumptive triggers that induce TDMD of miR-322/503 have remained elusive until now. We show here that Plagl1 and Lrrc58 are the long-sought trigger RNAs for TDMD of miR-322 and miR-503, respectively.
July 2, 2025 at 4:17 PM
But the presumptive triggers that induce TDMD of miR-322/503 have remained elusive until now. We show here that Plagl1 and Lrrc58 are the long-sought trigger RNAs for TDMD of miR-322 and miR-503, respectively.
miR-322/503 were among the first miRNAs found to have short half-lives (Rissland et al., Mol Cell 2011). Moreover, we showed that a major phenotype in Zswim8 KO mice, embryonic growth restriction, is attributable to upregulation of miR-322/503 (Jones et al., Genes Dev, 2023).
July 2, 2025 at 4:17 PM
miR-322/503 were among the first miRNAs found to have short half-lives (Rissland et al., Mol Cell 2011). Moreover, we showed that a major phenotype in Zswim8 KO mice, embryonic growth restriction, is attributable to upregulation of miR-322/503 (Jones et al., Genes Dev, 2023).
Here, we applied a method called AGO-CLASH, which enables the detection of bona fide miRNA binding sites across the transcriptome. This revealed the triggers for TDMD of miR-322 and miR-503 in mice. These miRNAs are of particular interest for several reasons.
July 2, 2025 at 4:17 PM
Here, we applied a method called AGO-CLASH, which enables the detection of bona fide miRNA binding sites across the transcriptome. This revealed the triggers for TDMD of miR-322 and miR-503 in mice. These miRNAs are of particular interest for several reasons.
Although it is presumed that each of these miRNAs has an associated trigger RNA that activates ZSWIM8-mediated degradation, the identification of TDMD triggers has proven to be a very challenging problem, with only four mammalian trigger RNAs reported to date.
July 2, 2025 at 4:17 PM
Although it is presumed that each of these miRNAs has an associated trigger RNA that activates ZSWIM8-mediated degradation, the identification of TDMD triggers has proven to be a very challenging problem, with only four mammalian trigger RNAs reported to date.
ZSWIM8 and its orthologs are required for normal development in flies, worms, and mice and, accordingly, many miRNAs are controlled by this mechanism across these species. For example, more than 50 ZSWIM8-regulated miRNAs have been identified in mouse tissues.
July 2, 2025 at 4:17 PM
ZSWIM8 and its orthologs are required for normal development in flies, worms, and mice and, accordingly, many miRNAs are controlled by this mechanism across these species. For example, more than 50 ZSWIM8-regulated miRNAs have been identified in mouse tissues.