Evidence map›Paper›PMID 40245860›Full record

ArticleCell2025

Rewriting regulatory DNA to dissect and reprogram gene expression.

Gabriella E Martyn, Michael T Montgomery, Hank Jones, Katherine Guo, Benjamin R Doughty, Johannes Linder, Deepa Bisht, Fan Xia, Xiangmeng S Cai, Ziwei Chen and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.

0numbers the graph read from it
0cells of the map it votes in
39citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

39 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
  4. Synthetic Regulatory Genomics.Annual review of genomics and human genetics · 2026
    Review
  5. Genetic influences on haematopoiesis.Nature reviews. Genetics · 2026
    Review
  6. Review
  7. Article
  8. Article
  9. Article
  10. Article
  11. Enhancer hubs govern chromatin topology and Th17 cell identity.bioRxiv : the preprint server for biology · 2026
    Article
  12. Article
  13. Review
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Gabriella E MartynDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA 94305, USA.
Michael T MontgomeryDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA 94305, USA.
Hank JonesDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA 94305, USA.
Katherine GuoDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA 94305, USA.
Benjamin R DoughtyDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Johannes LinderCalico Life Sciences LLC, South San Francisco, CA 94080, USA.
Deepa BishtDepartment of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA.
Fan XiaDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA 94305, USA.
Xiangmeng S CaiDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
Ziwei ChenDepartment of Computer Science, Stanford University, Stanford, CA 94305, USA.
Kelly CochranDepartment of Computer Science, Stanford University, Stanford, CA 94305, USA.
Kathryn A LawrenceDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Glen MunsonNovo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Anusri PampariDepartment of Computer Science, Stanford University, Stanford, CA 94305, USA.
Charles P FulcoBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Nidhi SahniDepartment of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA; Quantitative and Computational Biosciences Program, Baylor College of Medicine, Houston, TX 77030, USA.
David R KelleyCalico Life Sciences LLC, South San Francisco, CA 94080, USA.
Eric S LanderBroad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Anshul KundajeDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
Jesse M EngreitzDepartment of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA 94305, USA; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: engreitz@stanford.edu.

Funding

Stanford Center for Connecting DNA Variants to Function and PhenotypeUM1HG011972 · NHGRI · STANFORD UNIVERSITY · PI JESSE M ENGREITZ, THOMAS QUERTERMOUS · 2021 to 2026
$10.5M
Linking genome variation to transcriptional network dynamics in human B cellsU01HG012041 · NHGRI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Jishnu Das, HARINDER SINGH · 2021 to 2026
$6.1M
Predicting context-specific molecular and phenotypic effects of genetic variation through the lens of the cis-regulatory codeU01HG012069 · NHGRI · STANFORD UNIVERSITY · PI Anshul Kundaje · 2021 to 2026
$3.9M
Systematic mapping and prediction of gene-enhancer connectionsR00HG009917 · NHGRI · STANFORD UNIVERSITY · PI ENGREITZ, JESSE M · 2020 to 2022
$796k
Systematic mapping and prediction of gene-enhancer connectionsK99HG009917 · NHGRI · BROAD INSTITUTE, INC. · PI ENGREITZ, JESSE M · 2018 to 2019
$65k
NHGRI NIH HHS K99 HG009917NHGRI NIH HHS R00 HG009917NHGRI NIH HHS U01 HG012041NHGRI NIH HHS U01 HG012069NHGRI NIH HHS UM1 HG011972
6 · The paper itself

Abstract

Regulatory DNA provides a platform for transcription factor binding to encode cell-type-specific patterns of gene expression. However, the effects and programmability of regulatory DNA sequences remain difficult to map or predict. Here, we develop variant effects from flow-sorting experiments with CRISPR targeting screens (Variant-EFFECTS) to introduce hundreds of designed edits to endogenous regulatory DNA and quantify their effects on gene expression. We systematically dissect and reprogram 3 regulatory elements for 2 genes in 2 cell types. These data reveal endogenous binding sites with effects specific to genomic context, transcription factor motifs with cell-type-specific activities, and limitations of computational models for predicting the effect sizes of variants. We identify small edits that can tune gene expression over a large dynamic range, suggesting new possibilities for prime-editing-based therapeutics targeting regulatory DNA. Variant-EFFECTS provides a generalizable tool to dissect regulatory DNA and to identify genome editing reagents that tune gene expression in an endogenous context.

Indexed as

DNAGene EditingGene Expression RegulationRegulatory Sequences, Nucleic AcidAnimalsBinding SitesClustered Regularly Interspaced Short Palindromic RepeatsCRISPR-Cas SystemsHEK293 CellsHumansMiceTranscription FactorsDNATranscription FactorsCRISPRenhancersgene regulationhigh-throughput screeningnon-coding variantspredictive modelsprime editingRNA FlowFISHsequence designtranscription factors

Identifiers

PMID40245860
PMCPMC12167154

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.