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Cited by 9Congenital heart defects researchGene Regulatory Network AnalysisDevelopmental Biology and Gene Regulation

Integrated modeling framework reveals co-regulation of transcription factors, miRNAs and lncRNAs on cardiac developmental dynamics

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Li, Shumin, Yan, Bin, Wu, Binbin, Su, Junhao, Lu, Jianliang, Lam, Tak-Wah, Boheler, Kenneth R., Poon, Ellen Ngar-Yun +1 more·2023·Stem Cell Research & Therapy
DOI 10.1186/s13287-023-03442-0PMC PMC10500942
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Abstract

Aims: Dissecting complex interactions among transcription factors (TFs), microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are central for understanding heart development and function. Although computational approaches and platforms have been described to infer relationships among regulatory factors and genes, current approaches do not adequately account for how highly diverse, interacting regulators that include noncoding RNAs (ncRNAs) control cardiac gene expression dynamics over time. Methods: To overcome this limitation, we devised an integrated framework, cardiac gene regulatory modeling (CGRM) that integrates LogicTRN and regulatory component analysis bioinformatics modeling platforms to infer complex regulatory mechanisms. We then used CGRM to identify and compare the TF-ncRNA gene regulatory networks that govern early- and late-stage cardiomyocytes (CMs) generated by in vitro differentiation of human pluripotent stem cells (hPSC) and ventricular and atrial CMs isolated during in vivo human cardiac development. Results: Comparisons of in vitro versus in vivo derived CMs revealed conserved regulatory networks among TFs and ncRNAs in early cells that significantly diverged in late staged cells. We report that cardiac genes (“heart targets”) expressed in early-stage hPSC-CMs are primarily regulated by MESP1, miR-1, miR-23, lncRNAs NEAT1 and MALAT1, while GATA6, HAND2, miR-200c, NEAT1 and MALAT1 are critical for late hPSC-CMs. The inferred TF-miRNA-lncRNA networks regulating heart development and contraction were similar among early-stage CMs, among individual hPSC-CM datasets and between in vitro and in vivo samples. However, genes related to apoptosis, cell cycle and proliferation, and transmembrane transport showed a high degree of divergence between in vitro and in vivo derived late-stage CMs. Overall, late-, but not early-stage CMs diverged greatly in the expression of “heart target” transcripts and their regulatory mechanisms. Conclusions: In conclusion, we find that hPSC-CMs are regulated in a cell autonomous manner during early development that diverges significantly as a function of time when compared to in vivo derived CMs. These findings demonstrate the feasibility of using CGRM to reveal dynamic and complex transcriptional and posttranscriptional regulatory interactions that underlie cell directed versus environment-dependent CM development. These results with in vitro versus in vivo derived CMs thus establish this approach for detailed analyses of heart disease and for the analysis of cell regulatory systems in other biomedical fields.

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  • Myocardial cells differentiated from human pluripotent stem cells autonomously regulate during early development.

    “Myocardial cells differentiated from human pluripotent stem cells autonomously regulate during early development.”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [122]

    The Methods (Time series genome-wide expression data of mRNAs; page unavailable) define the early differentiation period for human pluripotent stem cell-derived cardiomyocytes. The Results (Co-regulation of TFs with ncRNAs on hESC/hiPSC-CM differentiation; page unavailable) describe regulatory programs associated with early cardiac development, but our copy does not establish that the cells regulate themselves autonomously. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • miR-23 and lncRNA Malat1 can regulate early expression of cardiac genes, thereby influencing cardiac development and contraction.

    “miR-23 and lncRNA Malat1 can regulate early expression of cardiac genes, thereby influencing cardiac development and contraction [122].”

    From Recent advances of miR-23 in human diseases and growth development (2025) · cites this paper as [122]

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Research works printed but not linked: 48

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Authors
Li, S., Yan, B., Wu, B., Su, J., Lu, J., Lam, T.-W., Boheler, K. R., Poon, E. N.-Y., & Luo, R.
Affiliations
  • University of Hong Kong (HK)
  • Chinese University of Hong Kong (HK)
  • Johns Hopkins University (US)
Corresponding author
  • Boheler, Kenneth R.
  • Poon, Ellen Ngar-Yun
  • Luo, Ruibang
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-09-13
Volume
14
Issue
1
Pages
247-247
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-023-03442-0
PMC
PMC10500942
OpenAlex
W4386709739
Cited by
9
References
49
Citations by year
2026: 1 · 2025: 3 · 2024: 5
FWCI
0.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Research Grants Council, University Grants Committee (17113721, 24100421)
  • National Science Foundation (2135907)
  • National Institutes of Health (R01-HL152249)
  • Health and Medical Research Fund (8191456)
  • The Chinese University of Hong Kong Research Committee Direct Grant (2021.006)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
heart development, transcription factors, microRNA, long non-coding RNA, cardiomyocytes, human pluripotent stem cell-derived cardiomyocytes, Mesp1, miR-1, miR-23, miR-200c, NEAT1, MALAT1, GATA6, Hand2, post-transcriptional regulation, cardiomyocyte differentiation
MeSH terms
Heart Ventricles, Humans, Transcription Factors, Myocytes, Cardiac, MicroRNAs, RNA, Long Noncoding

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