Josh Mendell

Congratulations to Kate, Hari, and all authors!

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...

And check out related work from the Bartel lab (@bartellab.bsky.social) 👇
www.biorxiv.org/content/10.1...

Regulated decay of microRNAs plays a critical role in controlling body size in mammals! Check out our new paper in @genesdev.bsky.social and see thread previously posted with our pre-print 👇 for more info. Congrats to Collette LaVigne, Jaeil Han, and all authors!
genesdev.cshlp.org/cgi/content/...

Thank you!

Thank you Davide!

Thank you Jinfan!

Thank you!

Thank you Julius!

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.

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.

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.

Oxidative stress sensing by the translation elongation machinery promotes production of detoxifying selenoproteins Selenocysteine, incorporated into polypeptides at recoded termination codons, plays an essential role in redox biology. Using GPX1 and GPX4, selenoenzymes that mitigate oxidative stress, as reporters,...

Colliding ribosomes are potent signals of cellular stress. But do cells use ‘programmed’ ribosome collisions to regulate gene expression? I’m excited to present a new story from my lab led by Frederick Rehfeld(@fred-rehfeld.bsky.social) which revealed that the answer is YES! Read on to find out how👇

Congratulations @kateodonnell-lab.bsky.social and Shayna!

#Worm25 Congratulations to Jacob (Ortega) for the Sydney Brenner thesis award!!! Truly a spectacular young scientist! Keep an eye out for him!!

Jacob is a postdoc in Josh Mendell’s lab at UTSW right now.

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.

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.

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.

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.

Our lab and the Bartel lab showed that this leads to recruitment of the ZSWIM8 ubiquitin ligase, which ubiquitylates the trigger-bound Argonaute (AGO) protein, resulting in decay of AGO by the proteasome and release and degradation of the associated miRNA.

In recent years, TDMD has emerged as a major mechanism that is critical for controlling microRNA (miRNA) expression during development in diverse metazoans. TDMD is activated when a miRNA binds to a specialized target RNA, referred to as a ‘trigger RNA’.

Plagl1 and Lrrc58 control mammalian body size by triggering target-directed microRNA degradation of miR-322 and miR-503 Precise control of microRNA (miRNA) expression is critical during development. An important mechanism of miRNA regulation is target-directed microRNA degradation (TDMD), a pathway in which the binding...

I am pleased to present our latest pre-print describing our identification of the long-sought triggers for target-directed microRNA degradation (TDMD) of miR-322 and miR-503, work led by Collette LaVigne and Jaeil Han. For more info, read on! 👇
www.biorxiv.org/content/10.1...

Congratulations Joana! This is fabulous work.

Special thanks to Tu Dan, He Zhang, Yujing Cheng, Frederick Rehfeld, and Jim Brugarolas for their critical contributions to this work and to @hhmi.org, NIH/NCI, CPRIT, and @thewelchfoundation.bsky.social for their essential and generous support! End/