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Josh Mendell @mendell-lab.bsky.social · Jul 17

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

Kate O'Donnell @kateodonnell-lab.bsky.social · Jul 17

This is my first post here. The past few months have been challenging for science, but I enjoy learning about others' work here and wanted to share our latest study. Congrats to postdoc Shayna Thomas-Jardin on her outstanding work published in Cancer Research @theaacr.bsky.social

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Reposted by Josh Mendell

Swathi Arur @swathiarur.bsky.social · Jun 29

#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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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).

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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’.

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Josh Mendell @mendell-lab.bsky.social · Jul 2

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...

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...

www.biorxiv.org

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Josh Mendell @mendell-lab.bsky.social · Apr 4

Congratulations Joana! This is fabulous work.

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Josh Mendell @mendell-lab.bsky.social · Apr 3

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/

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Josh Mendell @mendell-lab.bsky.social · Apr 3

Together, these findings highlight the functional versatility of snoRNA sequences, expand the known mechanisms through which noncoding RNAs orchestrate ribosome biogenesis, and illustrate how these functions are co-opted in cancer. 7/-

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Josh Mendell @mendell-lab.bsky.social · Apr 3

Through this mechanism, CRNDE promotes efficient ribosomal subunit maturation and export to the cytoplasm, supporting high levels of translation in cancer cells. 6/-

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Josh Mendell @mendell-lab.bsky.social · Apr 3

Instead, base-pairing of this element with pre-rRNA allows it to deliver the key 60S biogenesis factor eIF6, which binds directly to a sequence element in CRNDE adjacent to the UCE. 5/-

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Josh Mendell @mendell-lab.bsky.social · Apr 3

The UCE-containing variant of CRNDE localizes to the nucleolus and is required for 60S ribosomal subunit biogenesis. The UCE resembles a C/D box snoRNA and base-pairs with pre-rRNA. But the UCE does not guide 2'-O-methylation like canonical C/D box snoRNAs and is not processed into a small RNA. 4/-

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Josh Mendell @mendell-lab.bsky.social · Apr 3

This led to our finding that an alternatively-spliced variant of CRNDE containing an ultraconserved element (UCE), a sequence nearly perfectly conserved among all vertebrates, is required for proliferation in RCC. 3/-

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Josh Mendell @mendell-lab.bsky.social · Apr 3

This study describes how an ultra-conserved long noncoding RNA functions as a unique ribosome assembly factor. We began with a series of CRISPRi screens to identify long noncoding RNAs that are essential for growth and survival in renal cell carcinoma (RCC), a deadly malignancy. 2/-

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Josh Mendell @mendell-lab.bsky.social · Apr 3

It's difficult to focus on science with everything going on, but I still enjoy hearing about other people's work here, so I want to continue sharing ours. Congrats to postdoc Jong-Sun Lee for his outstanding work published in @cp-molcell.bsky.social! Details in thread👇
www.cell.com/molecular-ce...

An ultraconserved snoRNA-like element in long noncoding RNA CRNDE promotes ribosome biogenesis and cell proliferation

Cancer cells frequently enhance ribosome production to support rapid growth. Here, Lee et al. demonstrate that an isoform of lncRNA CRNDE containing an ultraconserved element (CRNDEUCE) promotes 60S r...

www.cell.com

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Josh Mendell @mendell-lab.bsky.social · Dec 19

Congrats on this elegant and important work Andrea!

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Reposted by Josh Mendell

Eugene Valkov @eugenevalkov.bsky.social · Dec 6

A nice journal club intro by Amy McDermott at PNAS to the excellent paper from @mendell-lab.bsky.social and colleagues #RNAsky #RNAbiology www.pnas.org/post/journal...

A new role for transfer RNA in protein synthesis

Translation entails ribosomes reading a gene’s messenger RNA transcript to generate a protein. Image credit: ART-ur/ Shutterstock.

www.pnas.org

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Josh Mendell @mendell-lab.bsky.social · Nov 23

Thank you!

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