Evidence map›Paper›PMID 38235591›Full record

ArticleCirculation2024

CRISPR Activation Reverses Haploinsufficiency and Functional Deficits Caused by

Shahnaz Ghahremani, Aditya Kanwal, Anthony Pettinato, Feria Ladha, Nicholas Legere, Ketan Thakar, Yanfen Zhu, Harianto Tjong, Andrea Wilderman, W Tom Stump and 5 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
4.9field-weighted citation impact, top 4% of its field
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

20 citing papers in PubMed, 21 citations in OpenAlex.

  1. Functional analysis ofMolecular therapy. Nucleic acids · 2026
    Article
  2. The dark genome in cardiovascular medicine.European heart journal · 2026
    Review
  3. Review
  4. Review
  5. Review
  6. Clinical translation of epigenome editing technologies.Current opinion in biomedical engineering · 2026
    Article
  7. Review
  8. Article
  9. Review
  10. Review
  11. Epigenome editing based treatment: Progresses and challenges.Molecular therapy : the journal of the American Society of Gene Therapy · 2026
    Review
  12. Review
  13. Article
  14. Review
  15. Advances in human induced pluripotent stem cell (hiPSC)-based disease modelling in cardiogenetics.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025
    Article
  16. Article
  17. Article
  18. Article
  19. Review
  20. Review
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

15 authors at 3 institutions in 1 country.

Shahnaz Ghahremani *The Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).
Aditya Kanwal *The Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).ORCID 0000-0002-8066-6798
Anthony PettinatoCardiology Center, University of Connecticut Health Center, Farmington (A.P., F.L., A.W., J.C., J.T.H.).ORCID 0000-0001-5623-8315
Feria LadhaCardiology Center, University of Connecticut Health Center, Farmington (A.P., F.L., A.W., J.C., J.T.H.).ORCID 0000-0002-8576-3976
Nicholas LegereThe Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).
Ketan ThakarThe Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).
Yanfen ZhuThe Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).
Harianto TjongThe Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).ORCID 0000-0003-1451-3918
Andrea WildermanCardiology Center, University of Connecticut Health Center, Farmington (A.P., F.L., A.W., J.C., J.T.H.).ORCID 0000-0002-4832-9476
W Tom StumpDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO (W.T.S., L.G., M.J.G.).
Lina GreenbergDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO (W.T.S., L.G., M.J.G.).ORCID 0000-0002-6066-3135
Michael J GreenbergDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO (W.T.S., L.G., M.J.G.).ORCID 0000-0003-1320-3547
Justin CotneyCardiology Center, University of Connecticut Health Center, Farmington (A.P., F.L., A.W., J.C., J.T.H.).ORCID 0000-0001-8230-2157
Chia-Lin WeiThe Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).
J Travis HinsonThe Jackson Laboratory for Genomic Medicine, Farmington, CT (S.G., A.K., N.L., K.T., Y.Z., H.T., C.-L.W., J.T.H.).ORCID 0000-0003-1455-113X
Jackson Laboratory · USUConn Health · USWashington University in St. Louis · US

Funding

Unraveling mechanisms of genome regulation to understand and improvehuman healthR35GM119465 · NIGMS · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI COTNEY, JUSTIN LEE · 2016 to 2025
$3.9M
Regulation of cardiac power output in health and diseaseR01HL141086 · NHLBI · WASHINGTON UNIVERSITY · PI GREENBERG, MICHAEL J · 2018 to 2022
$2.7M
SCGE Disease Models Studies Supplement: Cardioediting Ttntvs in a humanized mouse modelU01HL156349 · NHLBI · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI HINSON, JOHN TRAVIS · 2020 to 2022
$2.4M
Comprehensive Analysis of Allelic, Cellular and Molecular Heterogeneity in Human 3-Dimensional Cardiac Microtissues with MYH7 MutationsR01HL142787 · NHLBI · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI HINSON, JOHN TRAVIS · 2018 to 2021
$2.1M
Establishing and reversing the functional consequences of Titin truncation mutationsR01HL165220 · NHLBI · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · PI CAMPBELL, STUART G, HINSON, JOHN TRAVIS · 2022 to 2025
$2.1M
NHLBI NIH HHS R01 HL141086NHLBI NIH HHS R01 HL142787NHLBI NIH HHS R01 HL165220NHLBI NIH HHS U01 HL156349NIGMS NIH HHS R35 GM119465
6 · The paper itself

Abstract

background

methodsWe adapted CRISPR activation using dCas9-VPR to functionally interrogate TTNtv pathogenicity and develop a therapeutic in human cardiomyocytes and 3-dimensional cardiac microtissues engineered from induced pluripotent stem cell models harboring a dilated cardiomyopathy-associated TTNtv. We performed guide RNA screening with custom TTN reporter assays, agarose gel electrophoresis to quantify TTN protein levels and isoforms, and RNA sequencing to identify molecular consequences of TTN activation. Cardiomyocyte epigenetic assays were also used to nominate DNA regulatory elements to enable cardiomyocyte-specific TTN activation.

resultsCRISPR activation of TTN using single guide RNAs targeting either the

conclusionsTTN CRISPR activation rescued TTNtv-related functional deficits despite increasing truncated TTN levels, which provides evidence to support haploinsufficiency as a relevant genetic mechanism underlying heterozygous TTNtvs. CRISPR activation could be developed as a therapeutic to treat a large proportion of TTNtvs.

Indexed as

Cardiomyopathy, DilatedClustered Regularly Interspaced Short Palindromic RepeatsConnectinHaploinsufficiencyHumansMyocytes, CardiacRNA, Guide, CRISPR-Cas SystemsConnectinRNA, Guide, CRISPR-Cas SystemsTTN protein, humancardiomyopathy, dilatedclustered regularly interspaced short palindromic repeatsconnectinmyocytes, cardiac

Identifiers

PMID38235591
PMCPMC11031707
OpenAlexW4390984548

What OpenQuestion holds

Textmetadata
LicenceTDM
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.