Evidence map›Paper›PMID 38811842›Full record

ArticleNature genetics2024

Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells.

Cody T Mowery, Jacob W Freimer, Zeyu Chen, Salvador Casaní-Galdón, Jennifer M Umhoefer, Maya M Arce, Ketrin Gjoni, Bence Daniel, Katalin Sandor, Benjamin G Gowen and 12 more

Abstract read
In one paragraph

Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing 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

13 citing papers in PubMed.

  1. Article
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  5. Enhancer hubs govern chromatin topology and Th17 cell identity.bioRxiv : the preprint server for biology · 2026
    Article
  6. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors.

Cody T MoweryMedical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA.
Jacob W FreimerGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-9239-2272
Zeyu ChenDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Salvador Casaní-GaldónDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8714-3001
Jennifer M UmhoeferBiomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Maya M ArceBiomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0003-4234-9908
Ketrin GjoniGladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
Bence DanielGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-2410-8767
Katalin SandorGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.ORCID http://orcid.org/0000-0003-2892-4865
Benjamin G GowenInnovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
Vinh NguyenGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
Dimitre R SimeonovBiomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Christian M GarridoGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
Gemma L CurieInnovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
Ralf SchmidtGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-6697-0363
Zachary SteinhartGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
Ansuman T SatpathyGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-5167-537X
Katherine S PollardGladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
Jacob E CornInnovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.ORCID http://orcid.org/0000-0002-7798-5309
Bradley E BernsteinDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Chun Jimmie YeGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. jimmie.ye@ucsf.edu.ORCID http://orcid.org/0000-0001-6560-3783
Alexander MarsonGladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. alexander.marson@ucsf.edu.ORCID http://orcid.org/0000-0002-2734-5776

Funding

MEDICAL SCIENTIST TRAINING PROGRAMT32GM007618 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ANDERSON, MARK S · 1985 to 2020
$29.6M
Research BaseP30DK063720 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GERMAN, MICHAEL S · 2003 to 2019
$21.8M
DIABETES, ENDOCRINOLOGY &METABOLISM TRAINING PROGRAMT32DK007418 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI EDWARD C HSIAO · 1986 to 2026
$14.3M
Inherited T cell defects: Diagnosis, Mechanisms and TreatmentsP01AI138962 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI WIEST, DAVID L. · 2020 to 2024
$11.3M
MOLECULAR AND CELLULAR IMMUNOLOGYT32AI007334 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CYSTER, JASON G · 1988 to 2023
$11.0M
RESOURCE-BASED CENTER FOR THE ADVANCEMENT OF PRECISION MEDICINE IN RHEUMATOLOGYP30AR070155 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Mary C Nakamura · 2016 to 2026
$8.2M
Integration of genetic association mapping and functional data to elucidate genetic mechanisms of diseaseR01HG008140 · NHGRI · STANFORD UNIVERSITY · PI JONATHAN K PRITCHARD · 2016 to 2026
$7.3M
Restorative practice in repairing harm and promoting safe and inclusive practices in the laboratory.T32GM136547 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Adrian Erlebacher, Anita Sil · 2020 to 2026
$4.5M
Mapping gene-by-environment interactions using multiplexed single cell RNA-sequencingR01HG011239 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI YE, CHUN JIMMIE · 2020 to 2023
$4.1M
Genetic determinants of 4D genome folding in human cardiac developmentU01HL157989 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI BRUNEAU, BENOIT GAETAN, POLLARD, KATHERINE S. · 2020 to 2024
$3.8M
Genetic regulation and immunological function of ERAP2 haplotypesR01AI136972 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI YE, CHUN JIMMIE · 2018 to 2022
$3.5M
Identification and characterization of inflammatory bowel disease causal variantsR01DK129364 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Hailiang Huang · 2022 to 2026
$3.4M
NCI NIH HHS F99 CA234842NCI NIH HHS K00 CA234842NHGRI NIH HHS R01 HG008140NHGRI NIH HHS R01 HG011239NHLBI NIH HHS U01 HL157989NIAID NIH HHS F30 AI157167NIAID NIH HHS P01 AI138962NIAID NIH HHS R01 AI136972NIAID NIH HHS T32 AI007334NIAMS NIH HHS P30 AR070155NIDDK NIH HHS P30 DK063720NIDDK NIH HHS R01 DK129364NIDDK NIH HHS T32 DK007418NIGMS NIH HHS T32 GM007618NIGMS NIH HHS T32 GM136547NIH HHS S10 OD021822NIH HHS S10 OD028511
6 · The paper itself

Abstract

Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.

Indexed as

CD28 AntigensChromatinCTLA-4 AntigenGene Expression RegulationCCCTC-Binding FactorCRISPR-Cas SystemsHumansInducible T-Cell Co-Stimulator ProteinT-LymphocytesCCCTC-Binding FactorCD28 AntigensChromatinCTLA-4 AntigenCTLA4 protein, humanICOS protein, humanInducible T-Cell Co-Stimulator Protein

Identifiers

PMID38811842
PMCPMC11176074

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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.