Evidence map›Paper›PMID 39196225›Full record

ArticleNature cardiovascular research2024

A transcriptional enhancer regulates cardiac maturation.

Myo Htet, Shunyao Lei, Sheetal Bajpayi, Harshi Gangrade, Marios Arvanitis, Asimina Zoitou, Sean Murphy, Elaine Zhelan Chen, Navid Koleini, Brian Leei Lin and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature cardiovascular research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing 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

6 citing papers in PubMed.

  1. Article
  2. Article
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  4. Review
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  6. 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

12 authors.

Myo HtetDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-7653-1658
Shunyao LeiDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-7784-7766
Sheetal BajpayiDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
Harshi GangradeDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
Marios ArvanitisDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
Asimina ZoitouDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Sean MurphyDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-1960-2194
Elaine Zhelan ChenDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-4061-7921
Navid KoleiniDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
Brian Leei LinDepartment of Cell Biology, Neurobiology, and Anatomy and Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Chulan KwonDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA.
Emmanouil TampakakisDepartment of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD, USA. etampak1@jhmi.edu.ORCID http://orcid.org/0000-0003-3143-6459

Funding

PATHOPHYSIOLOGY OF MYOCARDIAL DISEASEST32HL007227 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI Chulan Kwon, WENDY S POST · 1985 to 2026
$21.2M
Transcriptomic Entropy to Quantify Maturation of PSC-Derived CardiomyocytesR01HL156947 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI KIM, DEOK-HO, KWON, CHULAN · 2021 to 2024
$2.3M
Engineering a power switch to study the contribution of stem cell-derived cardiomyocytes on heart regenerationK08HL145135 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI TAMPAKAKIS, EMMANOUIL · 2019 to 2023
$859k
From genotype to phenotype in a GWAS locus: the role of REST in atherosclerosisK08HL166690 · NHLBI · OHIO STATE UNIVERSITY · PI Marios Arvanitis · 2023 to 2026
$681k
TRPC6 inhibition therapy to rescue cardiac muscle dysfunction in muscular dystrophyK99HL155840 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI LIN, BRIAN LEEI · 2022 to 2023
$261k
American Heart Association (American Heart Association, Inc.) CDA34660077American Heart Association (American Heart Association, Inc.) TPA1058685Maryland Stem Cell Research Fund (MSCRF) 2023- MSCRFL-5984Maryland Stem Cell Research Fund (MSCRF) MSCRFD-6139NHLBI NIH HHS K08 HL145135NHLBI NIH HHS K08 HL166690NHLBI NIH HHS K99 HL155840NHLBI NIH HHS R01 HL156947NHLBI NIH HHS T32 HL007227U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) 5K08HL166690U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) HL-145135U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL156947U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) T32HL007227
6 · The paper itself

Abstract

Cardiomyocyte maturation is crucial for generating adult cardiomyocytes and the application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). However, regulation at the cis-regulatory element level and its role in heart disease remain unclear. Alpha-actinin 2 (ACTN2) levels increase during CM maturation. In this study, we investigated a clinically relevant, conserved ACTN2 enhancer's effects on CM maturation using hPSC and mouse models. Heterozygous ACTN2 enhancer deletion led to abnormal CM morphology, reduced function and mitochondrial respiration. Transcriptomic analyses in vitro and in vivo showed disrupted CM maturation and upregulated anabolic mammalian target for rapamycin (mTOR) signaling, promoting senescence and hindering maturation. As confirmation, ACTN2 enhancer deletion induced heat shock protein 90A expression, a chaperone mediating mTOR activation. Conversely, targeting the ACTN2 enhancer via enhancer CRISPR activation (enCRISPRa) promoted hPSC-CM maturation. Our studies reveal the transcriptional enhancer's role in cardiac maturation and disease, offering insights into potentially fine-tuning gene expression to modulate cardiomyocyte physiology.

Indexed as

ActininCell DifferentiationEnhancer Elements, GeneticMyocytes, CardiacAnimalsCell LineGene Expression Regulation, DevelopmentalHSP90 Heat-Shock ProteinsHumansMicePhenotypeSignal TransductionTOR Serine-Threonine KinasesTranscription, GeneticActininACTN2 protein, humanHSP90 Heat-Shock ProteinsMTOR protein, humanTOR Serine-Threonine Kinases

Identifiers

PMID39196225
PMCPMC12306338

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Registered trials

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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.