Evidence map›Paper›PMID 41248983›Full record

ArticleCardiovascular research2026

Transcriptional readthrough at Atf4 locus suppresses Rps19bp1 and impairs heart development.

Zengming Zhang, Tongbin Wu, Zeyu Chen, Danni Chen, Zhengyu Liang, Christopher Adams, Yusu Gu, Mao Ye, Fhujjen Barroga, Sylvia Evans and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cardiovascular research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing 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

2 citing papers in PubMed.

  1. Review
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors.

Zengming ZhangDepartment of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Tongbin WuDepartment of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, 2150 Bleecker Street, Utica, NY 13501, USA.
Zeyu ChenDepartment of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.ORCID 0000-0003-3442-4162
Danni ChenDepartment of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Zhengyu LiangDepartment of Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Christopher AdamsDivision of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Yusu GuDepartment of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Mao YeDepartment of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Fhujjen BarrogaHerbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Sylvia EvansSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Xiaohai ZhouDepartment of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Ju ChenDepartment of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.ORCID 0000-0001-7674-4776

Funding

U of Calif, San Diego Neuroscience Microscopy ImagingP30NS047101 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G, ZHENG, BINHAI · 2003 to 2022
$9.0M
San Diego Skeletal Muscle Research CenterP30AR061303 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHEN, JU · 2011 to 2015
$3.3M
ATF4 a Novel Regulator of Cardiac DevelopmentR01HL164549 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Ju Chen · 2023 to 2026
$2.2M
The role of nucleo-cytoskeletal link proteins in skeletal muscleR01AR059334 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHEN, JU · 2010 to 2014
$1.7M
Gene Therapy for ALPK3 Cardiomyopathy Using MiniALPK3R01HL175344 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Ju Chen · 2024 to 2026
$1.6M
PRDM16 in cardiac developmentR01HL153032 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHEN, JU · 2020 to 2023
$1.6M
The Cardiac Role of Filamin CR01HL144872 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHEN, JU · 2019 to 2022
$1.6M
ALPK3 in cardiac function and diseaseR01HL146759 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHEN, JU · 2019 to 2022
$1.6M
BAG3 in Cardiac function and diseaseR01HL130295 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI CHEN, JU · 2016 to 2019
$1.6M
American Heart AssociationNational Institutes of Health SIG #S10 OD026929NHLBI NIH HHS R01 HL130295NHLBI NIH HHS R01 HL144872NHLBI NIH HHS R01 HL146759NHLBI NIH HHS R01 HL153032NHLBI NIH HHS R01 HL164549NHLBI NIH HHS R01 HL175344NIAMS NIH HHS P30 AR061303NIAMS NIH HHS R01 AR059334NINDS NIH HHS P30NS047101University of California, San Diego
6 · The paper itself

Abstract

aimsActivating transcription factor 4 (ATF4) functions as a transcriptional regulator in various cell types and tissues under both physiological and pathological conditions. While previous studies have linked ATF4 activation with promoting cardiomyocyte (CM) death in dilated cardiomyopathy (DCM), atrial fibrillation, and heart failure, its role in developing CMs remains unexplored. METHODS AND

resultsWe generated multiple distinct CM-specific (Atf4cKO(e2/3/pA) and Atf4cKO(e2)) and global Atf4 knockout (KO; Atf47del/7del and Atf41ins/1ins) mouse models targeting different Atf4 regions, as well as CM-specific deletion of Rps19bp1 to study cardiac phenotypes. Detailed morphological and molecular analyses were performed. Atf4cKO(e2/3/pA) [targeting exon 2-3 including the polyadenylation signal (polyA)] mice exhibited severe cardiac defects and died before E17.5, likely due to ectopic activation of the p53 signaling pathway resulting from Rps19bp1 downregulation, a potent suppressor of p53. Further investigation revealed that deleting the polyA signal of Atf4 in Atf4cKO(e2/3/pA) mice led to transcriptional readthrough, resulting in the formation of an Atf4-Cacna1i fusion transcript and Rps19bp1 downregulation. To avoid readthrough while abolishing ATF4 function, we introduced small indels into exon 3 of Atf4 in mice (Atf47del/7del and Atf41ins/1ins), which showed normal Rps19bp1 expression and cardiac morphology. Importantly, CM-specific deletion of Rps19bp1 recapitulated the cardiac defects and transcriptional change seen in Atf4cKO(e2/3/pA) mice.

conclusionWe found that the downregulation of Rps19bp1, not the loss of ATF4 function, underlies the cardiac phenotypes in Atf4cKO(e2/3/pA) mice. The reduced expression of Rps19bp1 in Atf4cKO(e2/3/pA) mice is likely due to the unintentional deletion of Atf4 polyA signal and subsequent transcriptional readthrough, underscoring the essential role of RPS19BP1, not ATF4, in cardiac development. Consistent Rps19bp1 downregulation has been observed in other tissue-specific Atf4 KO models utilizing the Atf4fl(e2/3/pA) allele, suggesting that previously reported Atf4 KO phenotypes may result from Atf4 transcriptional readthrough effects. These findings reveal a locus-dependent transcriptional interference mechanism and emphasize the importance of avoiding confounding cis effects in genetically engineered models.

Indexed as

Activating Transcription Factor 4HeartMyocytes, CardiacRibosomal ProteinsTranscription, GeneticAnimalsDisease Models, AnimalGene Expression Regulation, DevelopmentalMiceMice, KnockoutPhenotypeSignal TransductionTumor Suppressor Protein p53Activating Transcription Factor 4Atf4 protein, mouseRibosomal ProteinsTrp53 protein, mouseTumor Suppressor Protein p53ATF4heart developmentknockoutRps19bp1Transcriptional Readthrough

Identifiers

PMID41248983
PMCPMC13012809

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.