Evidence map›Paper›PMID 36705030›Full record

ArticleCirculation2023

In Vivo Dissection of Chamber-Selective Enhancers Reveals Estrogen-Related Receptor as a Regulator of Ventricular Cardiomyocyte Identity.

Yangpo Cao, Xiaoran Zhang, Brynn N Akerberg, Haiyun Yuan, Tomoya Sakamoto, Feng Xiao, Nathan J VanDusen, Pingzhu Zhou, Mason E Sweat, Yi Wang and 6 more

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

Article in Circulation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.

0numbers the graph read from it
0cells of the map it votes in
31citing papers in PubMed
5.8field-weighted citation impact, top 3% 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

31 citing papers in PubMed, 38 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Enhancer Dynamics for Gene Regulation in the Cardiovascular System.Arteriosclerosis, thrombosis, and vascular biology · 2026
    Review
  5. Article
  6. Review
  7. Article
  8. Review
  9. Article
  10. Article
  11. Article
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  13. Review
  14. Article
  15. Review
  16. AnFrontiers in genetics · 2025
    Article
  17. Cardiac Applications of CRISPR/AAV-Mediated Precise Genome Editing.bioRxiv : the preprint server for biology · 2024
    Article
  18. Article
  19. Review
  20. 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

16 authors at 4 institutions in 2 countries.

Yangpo Cao *Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).ORCID 0000-0001-7386-8247
Xiaoran Zhang *Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).ORCID 0000-0003-0979-7100
Brynn N Akerberg *Department of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).
Haiyun YuanDepartment of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangzhou, China (H.Y.).ORCID 0000-0002-8884-4202
Tomoya SakamotoCardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.S., D.P.K.).ORCID 0000-0001-8560-357X
Feng XiaoDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).ORCID 0000-0002-9084-9328
Nathan J VanDusenHerman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis (N.J.V.).ORCID 0000-0002-2636-7228
Pingzhu ZhouDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).
Mason E SweatDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).ORCID 0000-0002-5400-1266
Yi WangDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).
Maksymilian ProndzynskiDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).
Jian ChenDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).
Yan ZhangDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).
Peizhe WangDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).ORCID 0000-0003-4298-2471
Daniel P KellyCardiovascular Institute, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (T.S., D.P.K.).ORCID 0000-0002-3811-9491
William T PuDepartment of Cardiology, Boston Children's Hospital, Boston, MA (Y.C., X.Z., B.N.A., F.X., P.Z., M.E.S., Y.W., M.P., J.C., Y.Z., P.W., W.T.P.).ORCID 0000-0002-4551-8079
Boston Children's Hospital · USUniversity of Pennsylvania · USGuangdong Provincial People's Hospital · CNIndiana University – Purdue University Indianapolis · US

Funding

RESEARCH METHODS IN PEDIATRICS HEART DISEASET32HL007572 · NHLBI · CHILDREN'S HOSPITAL BOSTON · PI Sarah D DE FERRANTI, Jane W. Newburger · 1985 to 2026
$13.0M
REGULATION OF FATTY ACID OXIDATION DURING CARDIAC GROWTHR01HL058493 · NHLBI · WASHINGTON UNIVERSITY · PI KELLY, DANIEL PATRICK · 1998 to 2024
$10.6M
Transcriptional regulation of chamber selective gene expressionR01HL156503 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI William Tswenching Pu · 2021 to 2026
$4.0M
Regulation of Cardiomyocyte MaturationR01HL146634 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI PU, WILLIAM TSWENCHING · 2019 to 2022
$2.4M
Functional dissection of the regulatory network that governs cardiomyocyte maturationR00HL143194 · NHLBI · INDIANA UNIVERSITY INDIANAPOLIS · PI VANDUSEN, NATHAN JAMES · 2022 to 2024
$747k
NHLBI NIH HHS R00 HL143194NHLBI NIH HHS R01 HL058493NHLBI NIH HHS R01 HL146634NHLBI NIH HHS R01 HL156503NHLBI NIH HHS T32 HL007572
6 · The paper itself

Abstract

backgroundCardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined.

methodsWe nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus-mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-HiChIP on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP-mediated inactivation of ERRα and ERRγ in cardiomyocytes.

resultsWe identified 134 066 and 97 506 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus-mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27-anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs.

conclusionsWe identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi-transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.

Indexed as

HistonesMyocytes, CardiacChromatinEnhancer Elements, GeneticEstrogensGenome-Wide Association StudyHumansLysinePromoter Regions, GeneticTranscription FactorsChromatinEstrogensHistonesLysineTranscription Factorsenhancer elements, geneticepigenomicsERRalpha estrogen-related receptorgene expression regulationheart atriaheart ventricles

Identifiers

PMID36705030
PMCPMC10010668
OpenAlexW4318218420

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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.