About

Phillip A. Sharp is an Institute Professor and Professor of Biology Emeritus at MIT, affiliated with the Koch Institute for Integrative Cancer Research. His research has focused on various aspects of gene expression in mammalian cells, including transcription, the roles of non-coding RNAs such as microRNAs, and RNA splicing. He has investigated small, non-coding RNAs called microRNAs (miRNAs), which regulate over half of the genes in mammalian cells at the stages of translation and mRNA stability. Additionally, his work explores the processes underlying transcription from the anti-sense strand, known as divergent transcription, as well as the relationship between transcription elongation, RNA splicing, and chromatin modifications. Throughout his career, Sharp has made significant contributions to understanding gene regulation mechanisms and has been recognized with numerous awards, including the Nobel Prize in Physiology or Medicine in 1993, the National Medal of Science in 2004, and the AACR Award for Lifetime Achievement in Cancer Research in 2020.

Research topics

• Biology
• Genetics
• Computer Science
• Biophysics
• Internal medicine
• Medicine
• Physics
• Cell biology
• Computational biology

Selected publications

• Engineered prime editors with minimal genomic errors

  Nature · 2025-09-17 · 20 citations

  articleOpen access

  Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3′ ends1. These edited 3′ new strands must displace competing 5′ strands to install edits, yet a bias towards retaining the competing 5′ strands hinders efficiency and can cause indel errors2. Here we discover that nicked end degradation, consistent with competing 5′ strand destabilization, can be promoted by Cas9-nickase mutations that relax nick positioning. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next-generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 543:1. Engineered prime editor systems with reduced occurrences of unwanted insertions or deletions during genome editing are developed.

  PublisherOA PDFDOI

• Mutant p53 exploits enhancers to elevate immunosuppressive chemokine expression and impair immune checkpoint inhibitors in pancreatic cancer

  Immunity · 2025-07-01 · 22 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• RNA Dynamics Regulate Transcriptional Condensate Vivacity to Drive Gene Coordination

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-07 · 2 citations

  preprintOpen access

  Transcriptional condensates (TCs), enriched with Mediator, orchestrate super-enhancer (SE)-driven gene expression critical for cell identity. However, how their dynamic physical properties shape transcriptional activities remains unclear. Here, we reveal a previously unknown regulatory axis wherein dynamic features of enhancer RNA (eRNA), transcribed but rapidly degraded by the RNA exosome, maintain optimal TC fluidity and stability. Depletion of RNA exosome disrupts TC integrity, altering Mediator and Pol II colocalization, in embryonic stem cells. This TC perturbation attenuates proper transcriptional regulator loading and pause-release regulation, enhances transcriptional noise, and diminishes coordinated eRNA-mRNA expression for SE-associated genes. Multi-omics analyses, live-cell imaging, and computational modeling collectively demonstrate that RNA turnover modulates TC vivacity, facilitating widespread chromatin contacts between SE-containing active A compartments and coordinated transcriptional bursts across SE-associated genes. Our findings establish RNA-dependent condensate dynamics as an essential quality-control mechanism that fine-tunes global transcriptional coordination, maintaining cellular homeostasis and cell identity. Highlights: RNA exosome is required for the homeostasis of transcriptional condensates (TCs)RNA synthesis and decay optimize the fluidity and dynamic properties of TCsTCs maintain the transcriptional consistency of super-enhancer (SE) genesTCs support contacts of SE-containing A compartments for coordinated transcription.

  PublisherOA PDFDOI

• Abstract B087: Mutant-p53 amplifies Cxcl1 expression from distal enhancers blunting immune checkpoint inhibition efficacy in pancreatic cancer

  Cancer Research · 2024-01-16

  articleSenior author

  Abstract Pancreatic ductal Adenocarcinoma (PDAC) is an aggressive malignancy complicated by poor early diagnosis and a lack of response to traditional treatments. It is characterized by a desmoplastic stroma, a lack of infiltration and activation of T cells, and a low mutational burden. The genetic landscape of PDAC is defined by activating KRAS mutations (~90%) and p53 alterations (~70%), but the molecular switches perturbed by these genetic aberrations remain unclear. p53 missense mutations, unlike mutations resulting in the loss of p53, are considered to acquire tumor-supporting functions. But these novel functions remain uncharacterized. The ambiguity in the molecular mechanism of mutant-p53 is further exacerbated by the existence of various types of p53 mutations. The majority of p53 mutations are missense mutations in the DNA binding domain. The repertoire of transcription factors (TFs) it can interact with and the vast regulatory landscape of each TF—composed of gene promoters and distal enhancers—present obstacles in understanding the molecular mechanisms promoting PDAC. In this study, we examined how a common p53 missense mutation in PDAC plays a role in weakening the Immune checkpoint Inhibitors (ICIs) efficacy. Using cells derived from a genetically engineered mouse model (GEMM) of PDAC with activating KRAS mutation (KrasG12D/+) and a p53 missense mutation (p53R172H/-), we found that the PDAC tumorigenesis and resistance to ICIs are dependent on the mutant-p53. We used isogenic p53-null PDAC cells and the restoration of p53R172H in p53-null cells to demonstrate the role of p53R172H in controlling the expression of immunosuppressive chemokine genes such as Cxcl1. p53R172H deletion attenuated PDAC tumor growth, increased the influx of cytotoxic T-cells, and sensitized the tumor to ICIs. The p53R172H-mediated TME reprogramming was replicated by the deletion of the Cxcl1 gene, suggesting the anti-tumorigenic effect of p53R172H was mediated by the Cxcl1 gene. We probed the mechanism of Cxcl1 expression dependence on p53R172H. We found that in conjunction with NF-kB, p53R172H occupies the distal transcription regulatory elements (dTREs) of the Cxcl1 gene harboring NF-kB binding sites. Strikingly, deletion of the Cxcl1 dTREs in PDAC cells recapitulates the phenotypes of p53R172H deletion and Cxcl1 deletion in terms of tumor size, immune landscape of the TME, and ICI responsiveness. Furthermore, we examined the interplay between p53R172H and NF-kB and found that the p53R172H physically interacts with the NF-kB subunit RelA and facilitates its nuclear translocation. Overall, we characterize how a common p53 mutation in PDAC co-opts non-coding regulatory DNA to augment the expression of selective chemokine genes and establishes an immunosuppressive TME to shield the therapeutic benefits of ICIs. Citation Format: Dig B. Mahat, Heena Kumra, Emily Metcalf, Sarah Castro, Kim Nguyen1, Arundeep Singh, William W. Ho, Ivy Chen, Brandon Sullivan, Leon Yim, Enrico Moiso, Vikash Chauhan, Hernandez Moura Silva, Stefani Spranger, Rakesh Jain, Phillip A. Sharp. Mutant-p53 amplifies Cxcl1 expression from distal enhancers blunting immune checkpoint inhibition efficacy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B087.

  PublisherDOI

• Single-cell nascent RNA sequencing unveils coordinated global transcription

  Nature · 2024-06-05 · 108 citations

  articleOpen accessSenior author

  Abstract Transcription is the primary regulatory step in gene expression. Divergent transcription initiation from promoters and enhancers produces stable RNAs from genes and unstable RNAs from enhancers 1,2 . Nascent RNA capture and sequencing assays simultaneously measure gene and enhancer activity in cell populations 3 . However, fundamental questions about the temporal regulation of transcription and enhancer–gene coordination remain unanswered, primarily because of the absence of a single-cell perspective on active transcription. In this study, we present scGRO–seq—a new single-cell nascent RNA sequencing assay that uses click chemistry—and unveil coordinated transcription throughout the genome. We demonstrate the episodic nature of transcription and the co-transcription of functionally related genes. scGRO–seq can estimate burst size and frequency by directly quantifying transcribing RNA polymerases in individual cells and can leverage replication-dependent non-polyadenylated histone gene transcription to elucidate cell cycle dynamics. The single-nucleotide spatial and temporal resolution of scGRO–seq enables the identification of networks of enhancers and genes. Our results suggest that the bursting of transcription at super-enhancers precedes bursting from associated genes. By imparting insights into the dynamic nature of global transcription and the origin and propagation of transcription signals, we demonstrate the ability of scGRO–seq to investigate the mechanisms of transcription regulation and the role of enhancers in gene expression.

  PublisherOA PDFDOI

• Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-30 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Summary Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53 R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53 R172H . Mechanistically, we show that p53 R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53 R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB’s role in recruiting p53 R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC. Graphical Abstract

  PublisherOA PDFDOI

• Improved modeling of RNA-binding protein motifs in an interpretable neural model of RNA splicing

  Genome biology · 2024-01-16 · 14 citations

  articleOpen access

  Sequence-specific RNA-binding proteins (RBPs) play central roles in splicing decisions. Here, we describe a modular splicing architecture that leverages in vitro-derived RNA affinity models for 79 human RBPs and the annotated human genome to produce improved models of RBP binding and activity. Binding and activity are modeled by separate Motif and Aggregator components that can be mixed and matched, enforcing sparsity to improve interpretability. Training a new Adjusted Motif (AM) architecture on the splicing task not only yields better splicing predictions but also improves prediction of RBP-binding sites in vivo and of splicing activity, assessed using independent data.

  PublisherOA PDFDOI

• Engineered prime editors with minimal genomic errors

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-08-03 · 2 citations

  preprintOpen accessCorresponding

  Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3' ends. These edited 3' new strands must displace competing 5' strands to install edits, yet a bias toward retaining the competing 5' strands hinders efficiency and can cause indel errors. Using rational design of the constituent Cas9-nickase to reposition prime editor nicks, we discovered that competing 5' strands are destabilized to favor the edited 3' new strands. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next- generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 465:1. One Sentence Summary: Prime editors designed with repositioned DNA breaks nearly eliminate undesired genome editing errors.

  PublisherOA PDFDOI

• Supplementary Table 4 from The Octamer Binding Transcription Factor Oct-1 Is a Stress Sensor

  2023-03-30

  supplementary-materialsOpen accessSenior author

  Supplementary Table 4 from The Octamer Binding Transcription Factor Oct-1 Is a Stress Sensor

  PublisherDOI

• Improved modeling of RNA-binding protein motifs in an interpretable neural model of RNA splicing

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-20 · 1 citations

  preprintOpen access

  Summary Sequence-specific RNA-binding proteins (RBPs) play central roles in splicing decisions, but their exact binding locations and activities are difficult to predict. Here, we describe a modular splicing architecture that leverages in vitro -derived RNA affinity models for 79 human RBPs and the annotated human genome to produce improved models of RBP binding and activity. Binding and activity are modeled by separate Motif and Aggregator components that can be mixed and matched, enforcing sparsity to improve interpretability. Standard affinity models yielded reasonable predictions, but substantial improvements resulted from using a new Adjusted Motif (AM) architecture. While maintaining accurate modeling of in vitro binding, training these AMs on the splicing task yielded improved predictions of binding sites in vivo and of splicing activity, using independent crosslinking and massively parallel splicing reporter assay data. The modular structure of our model enables improved generalizability to other species (insects, plants) and to exons of different evolutionary ages.

  PublisherOA PDFDOI

Recent grants

• Regulation of mRNA Processing

  NIH · $9.9M · 1984–2022

• Stress and Proliferation States Impact MicroRNA-Mediated Regulation in Cancer

  NIH · $4.6M · 2008–2019

• NIH Grant U54CA151884

  NIH · $8.9M · 2016

• NIH Grant R01GM032467

  NIH · $869k · 1991

• NIH Grant R01AI032486

  NIH · $2.8M · 2003

Frequent coauthors

• C. Collard

  Institut Pluridisciplinaire Hubert Curien

  236 shared

• J. Andreä

  Institut Pluridisciplinaire Hubert Curien

  235 shared

• E. Conte

  Institut Pluridisciplinaire Hubert Curien

  234 shared

• D. Blöch

  Institut Pluridisciplinaire Hubert Curien

  232 shared

• E. C. Chabert

  Institut Pluridisciplinaire Hubert Curien

  221 shared

• M. Lethuillier

  Institute of Nuclear Physics of Lyon

  212 shared

• B. Ille

  Institute of Nuclear Physics of Lyon

  191 shared

• P. Verdier

  Institute of High Energy Physics

  190 shared

Labs

• Phillip A. Sharp LabPI

Awards & honors

• AACR Award for Lifetime Achievement in Cancer Research (2020…
• AACR Distinguished Award for Extraordinary Scientific Innova…
• Royal Society of London, Foreign Fellow (2011)
• National Science Foundation, National Medal of Science (2004…
• The Nobel Foundation, Nobel Prize in Physiology or Medicine…