Evidence map›Paper›PMID 28232072›Full record

ArticleJournal of molecular and cellular cardiology2017

BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility.

Monte S Willis, Darcy Wood Holley, Zhongjing Wang, Xin Chen, Megan Quintana, Brian C Jensen, Manasi Tannu, Joel Parker, Darwin Jeyaraj, Mukesh K Jain and 3 more

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

Article in Journal of molecular and cellular cardiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
1.2field-weighted citation impact, top 22% 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

10 citing papers in PubMed, 21 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Article
  6. Review
  7. Article
  8. Epigenetics in dilated cardiomyopathy.Current opinion in cardiology · 2019
    Review
  9. Article
  10. Article
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

13 authors at 6 institutions in 2 countries.

Monte S WillisMcAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: monte_willis@med.unc.edu.
Darcy Wood HolleyDepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Zhongjing WangMcAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
Xin ChenDepartment of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, PR China.
Megan QuintanaMcAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Brian C JensenMcAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
Manasi TannuDepartment of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, PR China.
Joel ParkerDepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Darwin JeyarajDepartment of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH 44106, USA.
Mukesh K JainDepartment of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH 44106, USA.
Julie A WolframDepartment of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Hyoung-Gon LeeDepartment of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA. Electronic address: hyoung-gon.lee@utsa.edu.
Scott J BultmanDepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: Scott_Bultman@med.unc.edu.
UNC Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill · USCase Western Reserve University · USShandong Provincial Hospital · CNThe University of Texas at San Antonio · USUniversity Hospitals Case Medical Center · US

Funding

Myocyte specific regulation of metabolism and the response to biomechanical forceR01HL104129 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI WILLIS, MONTE S · 2010 to 2018
$3.3M
Dietary Fiber, Gut Microflora, & Epigenetic Events that Prevent Colorectal CancerR01CA125237 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BULTMAN, SCOTT J · 2007 to 2011
$1.4M
NCI NIH HHS R01 CA125237NHLBI NIH HHS R01 HL104129
6 · The paper itself

Abstract

rationaleThe contractile dysfunction that underlies heart failure involves perturbations in multiple biological processes ranging from metabolism to electrophysiology. Yet the epigenetic mechanisms that are altered in this disease state have not been elucidated. SWI/SNF chromatin-remodeling complexes are plausible candidates based on mouse knockout studies demonstrating a combined requirement for the BRG1 and BRM catalytic subunits in adult cardiomyocytes. Brg1/Brm double mutants exhibit metabolic and mitochondrial defects and are not viable although their cause of death has not been ascertained.

objectiveTo determine the cause of death of Brg1/Brm double-mutant mice, to test the hypothesis that BRG1 and BRM are required for cardiac contractility, and to identify relevant downstream target genes. METHODS AND

resultsA tamoxifen-inducible gene-targeting strategy utilizing αMHC-Cre-ERT was implemented to delete both SWI/SNF catalytic subunits in adult cardiomyocytes. Brg1/Brm double-mutant mice were monitored by echocardiography and electrocardiography, and they underwent rapidly progressive ventricular dysfunction including conduction defects and arrhythmias that culminated in heart failure and death within 3weeks. Mechanistically, BRG1/BRM repressed c-Myc expression, and enforced expression of a DOX-inducible c-MYC trangene in mouse cardiomyocytes phenocopied the ventricular conduction defects observed in Brg1/Brm double mutants. BRG1/BRM and c-MYC had opposite effects on the expression of cardiac conduction genes, and the directionality was consistent with their respective loss- and gain-of-function phenotypes. To support the clinical relevance of this mechanism, BRG1/BRM occupancy was diminished at the same target genes in human heart failure cases compared to controls, and this correlated with increased c-MYC expression and decreased CX43 and SCN5A expression.

conclusionBRG1/BRM and c-MYC have an antagonistic relationship regulating the expression of cardiac conduction genes that maintain contractility, which is reminiscent of their antagonistic roles as a tumor suppressor and oncogene in cancer.

Indexed as

Heart Conduction SystemMyocardial ContractionAnimalsDNA HelicasesElectrocardiographyGene Expression ProfilingGene Expression RegulationHeart FailureHumansMiceMice, TransgenicMutationMyocytes, CardiacNuclear ProteinsProtein BindingProto-Oncogene Proteins c-mycDNA HelicasesNuclear ProteinsProto-Oncogene Proteins c-mycSmarca2 protein, mouseSmarca4 protein, mouseTranscription FactorsArrhythmiasBradycardiaBRG1BRMCardiac connexinsCardiomyocyte conductionc-MYCHeart failureSWI/SNF

Identifiers

PMID28232072
PMCPMC5415084
OpenAlexW2591402747

What OpenQuestion holds

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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.