David Bartel's Lab

David Bartel's Lab

@bartellab.bsky.social

David Bartel's lab @WhiteheadInst @MIT @HHMI | microRNAs, mRNAs, and other RNAs

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David Bartel's Lab
@bartellab.bsky.social

In the first, we measured deadenylation rates across ~39K human 3′ UTR sequences and found that the poly(A)-proximal sequence tunes PABPC1 binding propensity, which in turn modulates deadenylation rate. A PABP-1212 mutant lacking UTR binding abolishes this effect. www.biorxiv.org/content/10.6...

biorxiv.orgThe molecular determinants of PABPC-mediated deadenylation rateDeadenylation, the enzymatic shortening of the poly(A) tail, is typically the first committed step of mRNA decay. Deadenylation rates span nearly a 1000-fold range between transcripts and are governed...
David Bartel's Lab
@bartellab.bsky.social

In the second, we built a platform to rapidly replace endogenous PABPC1 & PABPC4 with designed variants in human cells. We leverage PABPC paralogs, domain deletions, PTM-disrupting mutants, and titrated variant expression to understand RRM4 in the cellular context. www.biorxiv.org/content/10.6...

biorxiv.orgDissection of Poly(A)-binding protein (PABPC) cellular function using degron-mediated depletion with replacementCytoplasmic poly(A)-binding proteins (PABPCs) are essential and highly abundant regulators of mRNA stability and translation, but their cellular functions have been difficult to dissect due to slow tu...
David Bartel's Lab
@bartellab.bsky.social

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

genesdev.cshlp.orgmRNA 3′ UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth A biweekly scientific journal publishing high-quality research in molecular biology and genetics, cancer biology, biochemistry, and related fields
David Bartel's Lab@bartellab.bsky.social

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

biorxiv.orgmRNA 3′ UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growthMicroRNAs 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...
David Bartel's Lab
@bartellab.bsky.social

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

tinyurl.comThe E3 ubiquitin ligase mechanism specifying targeted microRNA degradation - NatureTarget-directed microRNA degradation is driven by the atypical ZSWIM8–CUL3 E3 ubiquitin ligase that uses a two-RNA-factor authentication mechanism to specifically recognize AGO–miRNA–trigger...
David Bartel's Lab@bartellab.bsky.social

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)

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David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab
@bartellab.bsky.social

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)

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David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab reposted

Iain Cheeseman
@iaincheeseman.bsky.social

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...

wi.mit.eduAlternate proteins from the same gene contribute differently to health and rare disease | Whitehead InstituteIain 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...
David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab
@bartellab.bsky.social

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)

biorxiv.orgPlagl1 and Lrrc58 control mammalian body size by triggering target-directed microRNA degradation of miR-322 and miR-503Precise 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...
David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab reposted

Eugene Valkov
@eugenevalkov.bsky.social

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...

nature.comMultivalent interactions with CCR4–NOT and PABPC1 determine mRNA repression efficiency by tristetraprolin - Nature CommunicationsDeadenylation 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...
David Bartel's Lab
@bartellab.bsky.social

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.

David Bartel's Lab reposted

Iain Cheeseman
@iaincheeseman.bsky.social

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...

biorxiv.orgGlobal inhibition of deadenylation stabilizes the transcriptome in mitotic cellsIn 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...
David Bartel's Lab
@bartellab.bsky.social

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

Whitehead Institute@whiteheadinstitute.bsky.social

Our latest Postdoc Q&A features Michelle Frank from the Bartel lab. Michelle is interested in how the brain balances the ability to learn new things with the need for maintaining stable connections. wi.mit.edu/news/meet-wh... #WhiteheadPostdocProfiles @bartellab.bsky.social

David Bartel's Lab
@bartellab.bsky.social

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)

David Bartel's Lab reposted

Peter Wang
@wyppeter.bsky.social

Happy 2025! Excited to finally share our published slicing structure of human AGO2, the catalytic structure for RNAi by siRNAs and miRNAs. This was an amazing collab effort between @voslab.org and @bartellab.bsky.social with @amohamed98.bsky.social

Seychelle Vos@voslab.org

Our collaborative AGO2 work with @bartellab.bsky.social is published! Abdallah and Peter used cryo-EM and biochemistry to determine the structure of AGO2 in a slicing competent conformation with a fully paired RNA. Read more about it here: tinyurl.com/AGO2-slicing

tinyurl.comThe structural basis for RNA slicing by human Argonaute2Mohamed et al. report the cryoelectron microscopy structure of human AGO2 with fully paired guide RNA. Their analysis reveals the structural basis for the slicing activity that drives RNAi, showing that the slicing-competent conformation is achieved by domain movements and RNA-protein contacts distinct from those of conformational intermediates and prokaryotic homologs.
David Bartel's Lab
@bartellab.bsky.social

Check out our latest paper in collaboration with @voslab.org on the cryo-EM structure of slicing by human AGO2: tinyurl.com/AGO2-slicing

tinyurl.comThe structural basis for RNA slicing by human Argonaute2Mohamed et al. report the cryoelectron microscopy structure of human AGO2 with fully paired guide RNA. Their analysis reveals the structural basis for the slicing activity that drives RNAi, showing that the slicing-competent conformation is achieved by domain movements and RNA-protein contacts distinct from those of conformational intermediates and prokaryotic homologs.
Seychelle Vos@voslab.org

Our collaborative AGO2 work with @bartellab.bsky.social is published! Abdallah and Peter used cryo-EM and biochemistry to determine the structure of AGO2 in a slicing competent conformation with a fully paired RNA. Read more about it here: tinyurl.com/AGO2-slicing

tinyurl.comThe structural basis for RNA slicing by human Argonaute2Mohamed et al. report the cryoelectron microscopy structure of human AGO2 with fully paired guide RNA. Their analysis reveals the structural basis for the slicing activity that drives RNAi, showing that the slicing-competent conformation is achieved by domain movements and RNA-protein contacts distinct from those of conformational intermediates and prokaryotic homologs.
David Bartel's Lab
@bartellab.bsky.social

Bartel Lab bids a fond farewell to our incredible lab manager, Asia Stefano. Wishing you all the best on your new adventures in the Rocky Mountains, Asia—thank you for the amazing time we shared together!

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