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

TitleIntegrated modeling framework reveals co-regulation of transcription factors, miRNAs and lncRNAs on cardiac developmental dynamics.
Authors
KeywordsCardiac development and function
Data integration
Gene regulatory network
lncRNAs
miRNAs
Transcription factors
Issue Date13-Sep-2023
PublisherBioMed Central
Citation
Stem Cell Research and Therapy, 2023, v. 14, n. 1 How to Cite?
Abstract

AIMS\nMETHODS\nRESULTS\nCONCLUSIONS\nDissecting 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.\nTo 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.\nComparisons 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.\nIn 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.


Persistent Identifierhttp://hdl.handle.net/10722/337835
ISSN
2023 Impact Factor: 7.1
2023 SCImago Journal Rankings: 1.798
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, S-
dc.contributor.authorYan, B-
dc.contributor.authorWu, B-
dc.contributor.authorSu, J-
dc.contributor.authorLu, J-
dc.contributor.authorLam, TW-
dc.contributor.authorBoheler, KR-
dc.contributor.authorPoon, EN-
dc.contributor.authorLuo, R-
dc.date.accessioned2024-03-11T10:24:15Z-
dc.date.available2024-03-11T10:24:15Z-
dc.date.issued2023-09-13-
dc.identifier.citationStem Cell Research and Therapy, 2023, v. 14, n. 1-
dc.identifier.issn1757-6512-
dc.identifier.urihttp://hdl.handle.net/10722/337835-
dc.description.abstract<p>AIMS\nMETHODS\nRESULTS\nCONCLUSIONS\nDissecting 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.\nTo 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.\nComparisons 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.\nIn 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.</p>-
dc.languageeng-
dc.publisherBioMed Central-
dc.relation.ispartofStem Cell Research and Therapy-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCardiac development and function-
dc.subjectData integration-
dc.subjectGene regulatory network-
dc.subjectlncRNAs-
dc.subjectmiRNAs-
dc.subjectTranscription factors-
dc.titleIntegrated modeling framework reveals co-regulation of transcription factors, miRNAs and lncRNAs on cardiac developmental dynamics.-
dc.typeArticle-
dc.identifier.doi10.1186/s13287-023-03442-0-
dc.identifier.pmid37705079-
dc.identifier.scopuseid_2-s2.0-85171140144-
dc.identifier.volume14-
dc.identifier.issue1-
dc.identifier.eissn1757-6512-
dc.identifier.isiWOS:001189112600001-
dc.identifier.issnl1757-6512-

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