ArticleCell2022
Transcription factor protein interactomes reveal genetic determinants in heart disease.
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Article in Cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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55citing papers in PubMed
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55 citing papers in PubMed, 84 citations in OpenAlex.
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- Inhibition ofPediatric discovery · 2026Article
- Essential role of NONO-HOXA1-Wnt axis in cardiomyocyte differentiation.Nature communications · 2026Article
- Global Evaluation of Congenital Heart Disease-Associated Non-Coding Variants.Research square · 2026Article
- Comprehensive perturbation of transcription factors in human cardiomyocytes reveals the regulatory architecture of congenital heart disease.bioRxiv : the preprint server for biology · 2026Article
- Understanding normal cardiac morphogenesis and its disruptions: a journey through pathways.Frontiers in genetics · 2026Review
- Analysis of influencing factors of congenital heart disease in children in Luzhou, China: a case-control study.Frontiers in medicine · 2026Article
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- Functional architecture of cardiac TF regulatory landscapes in control of mammalian heart development.bioRxiv : the preprint server for biology · 2025Article
- Contribution of omics to the pathophysiology of diaphragmatic hernias: a narrative review.European journal of pediatrics · 2025Review
- A combined genomic arrhythmia propensity score delineates cumulative risk.Cell reports. Medicine · 2025Article
- GLYR1-mediated downregulation of lncRNA HSD11B1-AS1 promotes proliferation, migration, and invasion of breast cancer cells.Medical oncology (Northwood, London, England) · 2025Article
- Procollagen IIA mediates positive feedback control of the mouse cardiogenic transcriptional network.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Genetics of Congenital Heart Disease.Clinics in perinatology · 2025Review
- Single-nuclei multiomics analysis identifies abnormal cardiomyocytes in a murine model of cardiac development.Nature communications · 2025Article
- Gremlin1 repression-mediated mitochondrial network hyperfunction contributes to TCE-induced zebrafish cardiac defects.Cell communication and signaling : CCS · 2025Article
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Authors and funding
28 authors at 8 institutions in 2 countries.
Barbara Gonzalez-TeranGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Maureen PittmanGladstone Institutes, San Francisco, CA, USA; Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Franco FelixGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Reuben ThomasGladstone Institutes, San Francisco, CA, USA.
Desmond Richmond-BuccolaGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Ruth HüttenhainGladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
Krishna ChoudharyGladstone Institutes, San Francisco, CA, USA.
Elisabetta MoroniSCITEC-CNR, Milano, Italy.
Mauro W CostaGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Yu HuangGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Arun PadmanabhanGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Division of Cardiology, Department of Medicine, University of California, San Francisco, CA, USA.
Michael AlexanianGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Clara Youngna LeeGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Bonnie E J MavenGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, CA, USA.
Kaitlen Samse-KnappGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Sarah U MortonDivision of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Michael McGregorGladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
Casey A GiffordGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
J G SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA, USA.
Christine E SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
Bruce D GelbDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Giorgio ColomboUniversity of Pavia, Department of Chemistry, Pavia, Italy.
Bruce R ConklinGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
Brian L BlackCardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Benoit G BruneauGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA; Division of Cardiology, Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA.
Nevan J KroganGladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
Katherine S PollardGladstone Institutes, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA; Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. Electronic address: katherine.pollard@gladstone.ucsf.edu.
Deepak SrivastavaGladstone Institutes, San Francisco, CA, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA; Division of Cardiology, Department of Pediatrics, UCSF School of Medicine, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA. Electronic address: deepak.srivastava@gladstone.ucsf.edu.
Gladstone Institutes · USQB3 · USBoston Children's Hospital · USChild Health and Development Institute · USHarvard University · USHoward Hughes Medical Institute · USUniversity of California, San Francisco · USUniversity of Pavia · IT
Funding
Administrative Coordinating Center: Cardiovascular Development and Pediatric Cardiac Genomics ConsortiaU01HL131003 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI CNOTA, JAMES, OLLBERDING, NICHOLAS J · 2016 to 2024
$54.8MTranscriptional Networks During Cardiac DifferentiationP01HL089707 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI SRIVASTAVA, DEEPAK · 2008 to 2017
$20.4MThe Psychiatric Cell Map Initiative: Connecting Genomics, Subcellular Networks, and Higher Order PhenotypesU01MH115747 · NIMH · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAMPMANN, MARTIN, KROGAN, NEVAN J · 2018 to 2022
$19.6MCARDIOGENESIS--MOLECULAR MECHANISMSR01HL057181 · NHLBI · UNIVERSITY OF TEXAS SW MED CTR/DALLAS · PI DEEPAK SRIVASTAVA · 1997 to 2026
$14.0MProject 3: Control of cardiac transcription by MEF2 and myocardinP01HL146366 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI SRIVASTAVA, DEEPAK · 2019 to 2023
$13.7MPREDOCTORAL TRAINING IN DEVELOPMENTAL BIOLOGYT32HD007470 · NICHD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Todd Nystul · 1994 to 2026
$7.7MGenomic Effects on Right Ventricular Function, Clinical Features and Outcomes in CHDU01HL098147 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI NEWBURGER, JANE W., ROBERTS, AMY E · 2009 to 2024
$6.7MRegulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein.R01HL127240 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI MCKINSEY, TIMOTHY, SRIVASTAVA, DEEPAK · 2015 to 2022
$6.4MThe Epigenetic Landscape of Heart DevelopmentUM1HL098179 · NHLBI · J. DAVID GLADSTONE INSTITUTES · PI BRUNEAU, BENOIT GAETAN, POLLARD, KATHERINE S. · 2015 to 2019
$4.7MRegulation of Cardiac Development in Health and DiseaseUM1HL098166 · NHLBI · HARVARD MEDICAL SCHOOL · PI PENNACCHIO, LEN ALEXANDER, PU, WILLIAM TSWENCHING · 2015 to 2019
$4.4MJAX-Gladstone, SCGE Disease Models Studies SupplementU01ES032673 · NIEHS · J. DAVID GLADSTONE INSTITUTES · PI CONKLIN, BRUCE R · 2020 to 2022
$2.4MEXTRAMULAR RESEARCH FACILITIES CONSTRUCTIONC06RR018928 · NCRR · J. DAVID GLADSTONE INSTITUTES · PI MAHLEY, ROBERT W. · 2003 to 2003
$2.1MNCRR NIH HHS C06 RR018928NHLBI NIH HHS K08 HL157700NHLBI NIH HHS P01 HL089707NHLBI NIH HHS P01 HL146366NHLBI NIH HHS R01 HL057181NHLBI NIH HHS R01 HL127240NHLBI NIH HHS R03 HL150412NHLBI NIH HHS U01 HL098147NHLBI NIH HHS U01 HL131003NHLBI NIH HHS UM1 HL098166NHLBI NIH HHS UM1 HL098179NHLBI NIH HHS UM1 HL172717NICHD NIH HHS T32 HD007470NIEHS NIH HHS U01 ES032673NIMH NIH HHS U01 MH115747
Abstract
Congenital heart disease (CHD) is present in 1% of live births, yet identification of causal mutations remains challenging. We hypothesized that genetic determinants for CHDs may lie in the protein interactomes of transcription factors whose mutations cause CHDs. Defining the interactomes of two transcription factors haplo-insufficient in CHD, GATA4 and TBX5, within human cardiac progenitors, and integrating the results with nearly 9,000 exomes from proband-parent trios revealed an enrichment of de novo missense variants associated with CHD within the interactomes. Scoring variants of interactome members based on residue, gene, and proband features identified likely CHD-causing genes, including the epigenetic reader GLYR1. GLYR1 and GATA4 widely co-occupied and co-activated cardiac developmental genes, and the identified GLYR1 missense variant disrupted interaction with GATA4, impairing in vitro and in vivo function in mice. This integrative proteomic and genetic approach provides a framework for prioritizing and interrogating genetic variants in heart disease.
Indexed as
Heart Defects, CongenitalTranscription FactorsAnimalsGATA4 Transcription FactorMiceMutationNuclear ProteinsOxidoreductasesProteomicsT-Box Domain ProteinsGata4 protein, mouseGATA4 Transcription FactorGlyr1 protein, mouseNuclear ProteinsOxidoreductasesT-Box Domain ProteinsTranscription Factorscongenital heart diseasede novo variantsdisease variantsGATA4geneticsGLYR1NPACprotein interactome networksTBX5
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