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Cited by 116Congenital heart defects researchPluripotent Stem Cells ResearchCardiac electrophysiology and arrhythmias

Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease

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Kathiriya, Irfan S., Rao, Kavitha S., Iacono, Giovanni, Devine, W. Patrick, Blair, Andrew P., Hota, Swetansu K., Lai, Michael H., Garay, Bayardo I. +19 more·2021·Developmental Cell
DOI 10.1016/j.devcel.2020.11.020PMC PMC7878434

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Abstract

Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics-in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.

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  • In silico deletion of TBX5 in fetal cardiomyocytes more significantly impacted its direct targets (as defined by ChIP-seq) compared to indirect targets and housekeeping genes.

    “Analogously, in silico deletion of TBX5, another known congenital heart disease gene, in fetal cardiomyocytes23 more significantly impacted its direct targets (as defined by ChIP-seq34) compared to indirect targets and housekeeping genes (Extended Data Fig. 9f).”

    From Transfer learning enables predictions in network biology (2023) · cites this paper as [34]

    The Results sections on cardiomyocyte function and transcriptional responses report TBX5 loss-of-function in iPSC-derived cardiomyocytes and an association between TBX5-sensitive genes and TBX5 binding sites. They do not report an in silico deletion in fetal cardiomyocytes. The direct-versus-indirect-target comparison is pointed to the citing paper’s Extended Data Fig. 9f, rather than clearly attributed to this source. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In silico deletion of TBX5 was significantly more deleterious to previously reported TBX5 direct targets.

    “In silico deletion of TBX5 was significantly more deleterious to previously reported TBX5 direct targets34”

    From Transfer learning enables predictions in network biology (2023) · cites this paper as [34]

    The Results section, “Discrete transcriptional responses to reduced TBX5 dosage in cardiomyocytes” (page unavailable), reports that TBX5 occupancy was associated with dosage-vulnerable genes and that 61 of 85 stepwise dose-dependent genes were near TBX5 binding sites. It does not report an in silico TBX5 deletion or a statistically significant comparison showing greater harm to previously reported direct targets. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • In silico deletion of TBX5 was significantly more deleterious to previously reported TBX5 direct targets than to housekeeping genes or TBX5 indirect targets.

    “In silico deletion of TBX5 was significantly more deleterious to previously reported TBX5 direct targets34 than to housekeeping genes or TBX5 indirect targets.”

    From Transfer learning enables predictions in network biology (2023) · cites this paper as [34]

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Authors
Kathiriya, I. S., Rao, K. S., Iacono, G., Devine, W. P., Blair, A. P., Hota, S. K., Lai, M. H., Garay, B. I., Thomas, R., Gong, H. Z., Wasson, L. K., Goyal, P., Sukonnik, T., Hu, K. M., Akgun, G. A., Bernard, L. D., Akerberg, B. N., Gu, F., Li, K., Speir, M. L., Haeussler, M., Pu, W. T., Stuart, J. M., Seidman, C. E., Seidman, J. G., Heyn, H., & Bruneau, B. G.
Affiliations
  • Gladstone Institutes (US)
  • Barcelona Institute of Science and Technology (ES)
  • University of California, Santa Cruz (US)
  • Brigham and Women's Hospital (US)
  • Boston Children's Hospital (US)
  • Harvard University (US)
  • Universitat Pompeu Fabra (ES)
Corresponding author
  • Kathiriya, Irfan S.
  • Bruneau, Benoit G.
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2021-02
Volume
56
Issue
3
Pages
292-309.e9
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2020.11.020
PMC
PMC7878434
OpenAlex
W3112439613
Cited by
116
References
12
Citations by year
2026: 13 · 2025: 25 · 2024: 25 · 2023: 18 · 2022: 21 · 2021: 13 · 2020: 1
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • University of California, San Francisco
  • Ministerio de Ciencia, Innovación y Universidades (SAF2017-89109-P)
  • Instituto de Salud Carlos III
  • Silicon Valley Community Foundation (2018-182809)
  • Foundation for Anesthesia Education and Research
  • National Human Genome Research Institute (5U41HG002371)
  • National Center for Research Resources (C06 RR018928)
  • California Institute for Regenerative Medicine (RB4-05901)
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL114948, UM1HL098166, UM1HL098179, USCF CVRI 2T32HL007731-27)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
TBX5, haploinsufficiency, congenital heart disease, gene regulatory networks, cardiomyocyte differentiation, induced pluripotent stem cells, spatial transcriptomics, MEF2C, dosage sensitivity, heart development, transcriptional regulation
MeSH terms
Animals, Cell Differentiation, Heart Defects, Congenital, Heart Ventricles, Humans, Models, Biological, Mutation, Transcription, Genetic, Gene Dosage, Body Patterning, T-Box Domain Proteins, Myocytes, Cardiac, Mice, Gene Regulatory Networks, Haploinsufficiency, MEF2 Transcription Factors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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