About

David Bartel is a professor of biology at MIT and a core member of the Whitehead Institute. He is an investigator at the Howard Hughes Medical Institute. His research focuses on molecular pathways that regulate eukaryotic gene expression by affecting the stability or translation of mRNAs. Specifically, he studies microRNAs and other small RNAs that specify the destruction and/or translational repression of mRNAs. His work also involves studying mRNAs, with particular attention to their untranslated regions and poly(A) tails, and how these regions recruit and mediate regulatory phenomena. Dr. Bartel has made significant contributions to understanding the biochemical basis of microRNA targeting efficacy, the coupling between poly(A)-tail length and translational efficiency, and the mechanisms of target-directed microRNA degradation. His research has advanced knowledge of noncoding regulatory RNAs, their role in gene regulation, and their impact on cellular processes.

Research topics

• Biology
• Biochemistry
• Cell biology

Selected publications

• Global stabilization of the transcriptome in mitotic cells

  The EMBO Journal · 2026-04-09 · 1 citations

  articleOpen access

  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 aspects of mitosis require substantial adaptations to gene expression. During interphase, homeostatic control of mRNA levels involves a constant balance of transcription and degradation, with a median mRNA half-life of ~2-4 h. If such short half-lives persisted in mitosis, cells would be expected to rapidly deplete their transcriptome without new transcription. Here, we report that the transcriptome is globally stabilized during prolonged mitotic delays. Median mRNA half-lives are increased >4-fold during mitotic arrest compared to interphase, buffering mRNA levels in the absence of new synthesis. Moreover, poly(A) tail-length profiles change during mitotic arrest, strongly suggesting a partial mitotic repression of deadenylation. In contrast, siRNA-directed mRNA degradation machinery remains active. We further show that mitotic mRNA stabilization depends on PABPC1&4. Depletion of PABPC1&4 during mitotic arrest reduces mRNA stability and disrupts the cells' ability to maintain arrest, highlighting the critical physiological role of mitotic transcriptome buffering.

  PublisherOA PDFDOI

• PAL-AI reveals genetic determinants that control poly(A)-tail length during oocyte maturation, with relevance to human fertility

  Nature Communications · 2025-08-01 · 1 citations

  articleOpen accessSenior author

  In oocytes of mammals and other animals, gene regulation is mediated primarily through changes in poly(A)-tail length. Here, we introduce PAL-AI, an integrated neural network machine-learning model that accurately predicts tail-length changes in maturing oocytes of frogs and mammals. We show that PAL-AI learned known and previously unknown sequence elements and their contextual features that control poly(A)-tail length, enabling it to predict tail-length changes resulting from 3'-untranslated region single-nucleotide substitutions. It also predicted tail-length-mediated translational changes, allowing us to nominate genes important for oocyte maturation. When comparing predicted tail-length changes in human oocytes with genomic datasets of the All of Us Research Program and gnomAD, we found that genetic variants predicted to disrupt tail lengthening have been under negative selection in the human population, thereby linking mRNA tail lengthening to human female fertility.

  PublisherOA PDFDOI

• mRNA poly(A)-tail length is a battleground for coronavirus–host competition

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-10 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract 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 report that coronavirus infection causes cytoplasmic poly(A)-binding protein (PABPC) activity to become limiting, which preferentially destabilizes short-tailed host mRNAs, occurring before the action of virally encoded mRNA-decay factor nsp1. In this environment hostile to poly(A) tails, viral RNAs maintain a narrow tail-length distribution centering on 70–80 nucleotides across infection cycles. They do this through two mechanisms. First, viral tails are extended during RNA synthesis within double-membrane vesicles; second, viral tails are capped by a complex that includes PABPC1 and CSDE1 and slows tail shortening. Our findings suggest poly(A)-tail length is an arena of host– virus conflict, in which preserving tail lengths of viral mRNAs promotes their cytoplasmic dominance. Highlights PABPC1 becomes limiting during coronavirus infection Limiting PABPC1 promotes decay of short-tailed host mRNAs—independently of nsp1 The tail lengths of coronaviral mRNAs are extended during their synthesis in DMVs Viral tails are capped by PABPC1 and CSDE1, which protects against deadenylation

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• The G3BP stress-granule proteins reinforce the integrated stress response translation programme

  Nature Cell Biology · 2025-12-19 · 6 citations

  articleOpen accessSenior author

  When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs.

  PublisherDOI

• Functional microRNA targeting without seed pairing

  Nucleic Acids Research · 2025-10-14 · 4 citations

  articleOpen accessSenior author

  MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to serve as guides, directing binding to partially complementary sites in mRNAs, ultimately causing post-transcriptional repression. Complementarity to the miRNA seed (miRNA nucleotides 2-7) is typically necessary and sufficient for repression. Here, we investigate unusual sites with extensive complementarity to the miRNA 3' region (nucleotide 9 and onwards) but without complementarity to the seed. The top examples of these 3'-only sites bind as well as top canonical sites and impart similar repression, which can be further boosted by as few as 2-3 additional pairs to the miRNA seed. Despite these similarities, 3'-only sites have slower association and dissociation rates than seed-matched sites. They also impart different conformations to bound AGO-miRNA complexes than do seed-matched sites, and individual miRNAs differ substantially with respect to how well they bind their respective 3'-only sites. Thus, pairing to the seed is not always required for binding and repression, or for a target to gain access to the 3' region of the guide. For miRNAs that recognize 3'-only sites, those sites are estimated to constitute <1% of the set of endogenous target sites, a proportion resembling that of other rare but functional site types such as 3'-compensatory sites.

  PublisherDOI

• mRNA 3′ UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-06 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract 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 degradation (TDMD) requires ZSWIM8. Zswim8 −/− mice exhibit reduced growth and perinatal lethality, accompanied by stabilization of dozens of microRNAs. Nonetheless, studies of TDMD function in mammals have been limited because only two TDMD-triggering RNAs have been identified in mice. Here, we computationally identify and validate five new TDMD-triggering sites in mouse models. One site in Atp6v1g1 and two in Lpar4 direct degradation of miR-335-3p, which shows that in mammals, two sites in the same transcript, and multiple sites in different transcripts, can collaborate to destabilize a microRNA. Moreover, sites in Plagl1 and Lrrc58 direct degradation of miR-322 and miR-503, respectively. Mice lacking the Plagl1 and Lrrc58 sites exhibit reduced growth, demonstrating that target-directed degradation of miR-503 and miR-322 promotes mammalian growth. Both miR-335-3p and Plagl1 are maternally imprinted, implying that they participate in parental conflict, but their corresponding triggers or target microRNA partner are not imprinted. Thus, 3′ UTRs directly participate in parental conflict by engaging TDMD to access an additional layer of regulation within a network of imprinted and biallelic genes.

  PublisherDOI

• Derepression of a single microRNA target causes female infertility in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-29 · 1 citations

  preprintOpen access

  ABSTRACT The miR-200a and miR-200b families control mouse ovulation and are essential for female fertility. The ZEB1 transcription factor is a conserved target of both families and has been implicated as a key player in female fertility at multiple levels. Using gene-edited mice that express a miR-200a/b-resistant form of Zeb1 , we found that derepression of Zeb1 in the female pituitary caused decreased production of luteinizing hormone and anovulatory infertility. These phenotypes were accompanied by widespread changes in pituitary gene expression characterized by decreased levels of ZEB1 targets, which include the miR-200a/b miRNAs, as expected from the miR-200a/b–ZEB1 double-negative feedback loop. Also observed were increased levels of mesenchymal genes, neuronal genes, and miR-200a/b targets. These results show that a double-negative feedback loop centered on the miRNA regulation of a single transcription factor can significantly influence the expression of thousands of genes and have dramatic phenotypic consequences.

  PublisherOA PDFDOI

• Lysosomal RNA profiling reveals targeting of specific types of RNAs for degradation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-09 · 2 citations

  preprintOpen accessSenior author

  , the role of lysosomal RNA degradation in post-transcriptional gene regulation is not well understood. Here, we define RNASET2, PLD3, and both endogenous and exogenous RNase A family members as lysosomal RNases. Cells lacking these RNases accumulated large amounts of lysosomal RNA. Although all types of RNA can be found within lysosomes, SRP RNAs, Y RNAs, 5' TOP mRNAs, long-lived mRNAs, and mRNAs encoding membrane and secreted proteins were specifically enriched. All types of RNA depend on autophagy for lysosomal targeting, but the lysosomally-enriched RNAs are more sensitive to loss of autophagy, implying that selective mechanisms mediate their lysosomal entry. RNA stability measurements revealed that lysosomally-degraded transcripts also had autophagy-dependent changes in stability. In exploring how specific RNAs are targeted for lysosomal degradation, we found that the Alu domain of SRP RNAs is sufficient for targeting these RNAs to lysosomes in fashion that depends on its interactions with the SRP9 and SRP14 proteins. For mRNAs, 5' TOP motifs are sufficient to increase their targeting to lysosomes for degradation in a LARP1-dependent manner. Altogether, our results establish lysosomes as selective modulators of cellular RNA content.

  PublisherOA PDFDOI

• 5′ untranslated regions tune <i>Toxoplasma</i> translation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-14

  preprintOpen access

  ABSTRACT Some of the longest 5′ untranslated regions (UTRs) documented in eukaryotes belong to parasites of the phylum Apicomplexa. Translational regulation plays prominent roles in the development of these parasites, including the agents of toxoplasmosis ( Toxoplasma gondii ) and malaria. To understand the function of 5′ UTRs in apicomplexan translation, we performed high-resolution ribosome profiling of T. gondii in human fibroblasts. We show that parasite translation efficiency (TE) is largely controlled by 5′ UTR features and tuned by the number of upstream AUGs (uAUGs). Examination of ribosome occupancy reveals that, despite widespread assembly of parasite monosomes on uAUGs, ribosomes seldom translate uORFs. These determinants of translation are reaffirmed in a massively parallel reporter assay examining the effect of more than 30,000 synthetic 5′ UTRs in T. gondii . A model trained on these results accurately predicted the TE of newly designed 5′ UTRs. Together, this work defines the regulatory language of T. gondii translation, providing a framework to understand the evolution of exceptionally long 5′ UTRs in apicomplexans.

  PublisherOA PDFDOI

• Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders

  Science · 2025-07-17 · 9 citations

  article

  Aggregation-prone polyglycine-containing proteins produced from expanded GGC repeats are implicated in an emerging family of neurodegenerative disorders. In this study, we showed that polyglycine itself forms aggregates that incorporate endogenous glycine-rich proteins, including FAM98B, a component of the transfer RNA (tRNA) ligase complex (tRNA-LC) that harbors the most glycine-rich sequence in the human proteome. Through this glycine-rich intrinsically disordered region (IDR), polyglycine sequesters and depletes the tRNA-LC, disrupting tRNA processing. Accordingly, patient tissues revealed aggregate-associated FAM98B depletion and accumulation of aberrant tRNA splicing intermediates. Furthermore, Fam98b depletion in adult mice caused progressive motor coordination deficits and hindbrain pathology. Our data suggest that the FAM98B glycine-rich IDR mechanistically links previously disparate neurodegenerative disorders of protein aggregation and tRNA processing.

  PublisherDOI

Recent grants

• Post-transcriptional gene regulation

  NIH · $7.0M · 2016–2026

• NIH Grant R01GM067031

  NIH · $7.3M · 2016

• NIH Grant R56DK068348

  NIH · $230k · 2011

• RNA Conformation and Catalysis

  NIH · $2.3M · 2000–2016

• NIH Grant R24GM069512

  NIH · $1.7M · 2008

Frequent coauthors

• Stephen W. Eichhorn

  Harvard University

  94 shared

• Alexander O. Subtelny

  Harvard University

  88 shared

• Sean E. McGeary

  Center for Systems Biology

  85 shared

• Vikram Agarwal

  University of Washington

  69 shared

• Wendy K. Johnston

  Howard Hughes Medical Institute

  66 shared

• David E. Weinberg

  University of California, San Francisco

  65 shared

• Nelson C. Lau

  Boston University

  64 shared

• Charlie Y. Shi

  Whitehead Institute for Biomedical Research

  58 shared

Labs

• David Bartel LabPI

Education

• Ph.D., Virology

  Harvard University

  1993

• B.A., Biology

  Goshen College

  1982

Awards & honors

• Member, National Academy of Sciences (2011)
• HHMI Investigator (2005)
• National Academy of Sciences Award in Molecular Biology (200…
• AAAS Newcomb Cleveland Prize (2002)