Our work investigating mRNA 3' UTRs that trigger target-directed miRNA degradation is now published! genesdev.cshlp.org/content/earl...

Our work on the E3 ligase mechanism of target-directed microRNA degradation is now published! Amazing collaboration with Brenda Schulman’s lab led by @jakobfarnung.bsky.social and @elenaslo.bsky.social, with special thanks to @wyppeter.bsky.social, Lianne Blodgett, and Daniel Lin! tinyurl.com/Z8TDMD

Does the noncoding genome actually carry more genetic information than coding seqs? Motivated by this question we mutated every bp in the 10kb MYC locus. Results are even more exciting: Decoding the MYC locus reveals a druggable ultraconserved RNA element www.biorxiv.org/content/10.6...

Huge thanks to @maxewilkinson.bsky.social for making this work possible! (4/4)

In the process of solving this mystery, we discovered a new, atypical conformation of the spliceosome and discovered that the spliceosome has a surprising propensity to reassemble on excised linear introns in both stressed and unstressed conditions. (3/4)

In budding yeast cultured under saturation or other prolonged stresses, ~10% of introns accumulate post-splicing as stable, linear RNAs that are protected by the spliceosome. We set out to understand how these stable introns remain associated with the spliceosome and escape canonical RNA decay.(2/4)

We’re excited to share our latest preprint on the mechanism of excised linear intron stabilization in yeast! This work was led by PhD student @glennli.bsky.social and was a wonderful collaboration with @maxewilkinson.bsky.social. Link: www.biorxiv.org/content/10.6... (1/4)

First preprint of the year! New work from @jimmy-ly.bsky.social revealing unexpected roles for 5' UTR length in controlling alternate translational isoforms - important implications for both physiological cell function and rare disease. Small changes -> big impacts.

www.biorxiv.org/content/10.6...

We are looking for a postdoc to work on mechanisms of #RNA decay in cancer using #cryoEM with #nanobodies and #minibinders! Please RT

We find that disrupting the miR-200–ZEB1 double-negative feedback loop leads to anovulatory infertility and widespread gene expression changes in the mouse pituitary. This study demonstrates the dramatic phenotypic and molecular consequences of disrupting repression of a single miRNA target. (2/2)

Check our latest collaboration with the Kleaveland Lab (kleavelandlab.org), led by Joanna Stefano and Lara Elcavage: academic.oup.com/nar/article/... (1/2)

Huge thanks to Brenda Schulman and @jakobfarnung.bsky.social for the exceptionally collaborative effort from start to finish. We also thank @wyppeter.bsky.social, Lianne Blodgett, and Daniel Lin for their invaluable contributions to this work! (5/5)

Our results establish AGO binding and polyubiquitylation as the key regulatory steps of TDMD, define a unique class of cullin–RING E3 ligases that depend on CUL3 and ELOB/C, and reveal generalizable RNA- and protein-mediated interactions that specify AGO degradation with exquisite selectivity. (4/5)

We demonstrate selective binding of ZSWIM8 to a human AGO–microRNA–trigger complex for CUL3-mediated polyubiquitylation of the AGO protein. Furthermore, cryo-EM analyses reveal how ZSWIM8 recognizes the distinct AGO and RNA conformations shaped by pairing of the microRNA to the trigger. (3/5)

The ZSWIM8 E3 ligase was known to cause degradation of AGO–microRNA complexes bound to trigger RNAs. However, whether and how ZSWIM8 directly recognizes these complexes among the preponderance of non-trigger-bound AGO–microRNA complexes in the cell has been a mystery. (2/5)

We are thrilled to share our latest work uncovering the mechanistic basis of target-directed microRNA degradation (TDMD). This work was driven by @jakobfarnung.bsky.social and @elenaslo.bsky.social in a fantastic collaboration with Brenda Schulman's lab. tinyurl.com/E3TDMD (1/5)

Alternate proteins from the same gene contribute differently to health and rare disease | Whitehead Institute Iain Cheeseman and colleagues reveal the underappreciated role of single genes producing multiple proteins in atypical presentations of rare disease, and present case studies of affected patients thro...

From an accidental discovery of hidden biology to a new framework to understanding and diagnosing rare disease. Thrilled to share the most recent work from our lab and the amazing Jimmy Ly.

wi.mit.edu/news/alterna...

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...

Check out related work by the Mendell lab (@mendell-lab.bsky.social) and the Xie lab: www.biorxiv.org/content/10.1..., www.biorxiv.org/content/10.1... (3/3)

We identify 5 sites in 3' UTRs of mRNAs that trigger target-directed microRNA degradation (TDMD) of miR-335-3p, miR-322, and miR-503, uncovering noncoding functions of these mRNAs. This study positions TDMD within imprinted gene networks on the battleground of parental conflict (2/3)

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...

Check out the latest work from our lab, led by Daniel Lin and Lara Elcavage: www.biorxiv.org/content/10.1... (1/3)

We've uncovered two mechanisms that coronaviruses use to solve the “tailomere problem” and identified an mRNA degradation pathway that operates independently of viral protein nsp1. Many thanks to Eugene Valkov's lab (@eugenevalkov.bsky.social) for their help with this study.

mRNA poly(A)-tail length is a battleground for coronavirus–host competition Most eukaryotic mRNAs contain a poly(A) tail, which in post-embryonic cells enhances their stability. Many cytoplasmic RNA viruses also harbor poly(A) tails on their genomic RNA and mRNAs. Here, we re...

Check out the latest work from our lab, led by Arash Latifkar @ara-latifkar.bsky.social , www.biorxiv.org/content/10.1...

Since their discovery, we have known lysosomes possess RNase activity; however, their endogenous substrates were not known. Surprisingly we found preferential targeting of specific RNAs for lysosomal degradation by autophagy and identified sequence motifs that mediate their lysosomal targeting (2/2)

Lysosomal RNA profiling reveals targeting of specific types of RNAs for degradation Autophagy targets a wide variety of substrates for degradation within lysosomes. While lysosomes are known to possess RNase activity, the role of lysosomal RNA degradation in post-transcriptional gene...

Check out the latest work from Jordan Ray (@jordanray.bsky.social), a collaboration between our lab and David Sabatini’s lab. www.biorxiv.org/content/10.1... (1/2)

Multivalent interactions with CCR4–NOT and PABPC1 determine mRNA repression efficiency by tristetraprolin - Nature Communications Deadenylation leads to mRNA decay, with PABPC1 protecting the poly(A) tail, while tristetraprolin and CCR4–NOT promote deadenylation. Here, the authors describe how these three proteins interact to re...

Delighted to present our second paper of the year. This one explores the molecular mechanism of TTP, a key post-transcriptional regulator of AU-rich mRNAs. Work led and coordinated by @filippekovic.bsky.social, in collaboration with Perry Blackshear.

www.nature.com/articles/s41...

We developed a neural network machine-learning model that predicts poly(A) tail-length changes in frog, mouse, and human oocytes, revealing new regulatory motifs and showing that variants disrupting tail lengthening are under negative selection, thus linking tail-length control to human fertility.

PAL-AI reveals genetic determinants that control poly(A)-tail length during oocyte maturation, with relevance to human fertility - Nature Communications Gene regulation in oocytes relies heavily on poly(A) tail-length changes. Here, the authors develop PAL-AI, a neural network model that predicts tail-length changes, identifies regulatory motifs, and ...

Check out the latest study from our lab, led by Coffee Xiang (@coffeebond007.bsky.social) www.nature.com/articles/s41... (1/2)

Global inhibition of deadenylation stabilizes the transcriptome in mitotic cells In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique...

New preprint! We solve a mystery you didn't know existed. Mitotic cells lack new transcription but require ongoing translation. Interphase mRNA half life is only 2-4 hrs. So how do cells arrest in mitosis for hours without depleting their transcriptomes?

www.biorxiv.org/content/10.1...

Don’t miss this Q&A with Dr. Michelle Frank (@michelle-frank.bsky.social), an awesome postdoc in our lab!

We report that some miRNAs are capable of high affinity binding to 3′-only sites (stretches of extensive perfect pairing to the 3′ region, without any pairing to the miRNA seed) and that these sites are functional, imparting post-transcriptional repression to site-containing reporter mRNAs. (2/2)