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Article: Integrated transcriptomics and regulatory network analyses identify microRNA-200c as a novel repressor of differentiation and maturation of human pluripotent stem cell-derived cardiomyocytes

TitleIntegrated transcriptomics and regulatory network analyses identify microRNA-200c as a novel repressor of differentiation and maturation of human pluripotent stem cell-derived cardiomyocytes
Authors
KeywordsBioinformatics methods
Gene regulatory network
miRNA-200c
Pluripotent stem cell-derived cardiomyocyte differentiation and maturation
Transcription factor
Issue Date2018
PublisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.org
Citation
Cardiovascular Research, 2018, v. 114 n. 6, p. 894-906 How to Cite?
AbstractAims MicroRNAs (miRNAs) are crucial for the post-transcriptional control of protein-encoding genes and together with transcription factors (TFs) regulate gene expression; however, the regulatory activities of miRNAs during cardiac development are only partially understood. In this study, we tested the hypothesis that integrative computational approaches could identify miRNAs that experimentally could be shown to regulate cardiomyogenesis. Methods and results We integrated expression profiles with bioinformatics analyses of miRNA and TF regulatory programs to identify candidate miRNAs involved with cardiac development. Expression profiling showed that miR-200c, which is not normally detected in adult heart, is progressively down-regulated both during cardiac development and in vitro differentiation of human embryonic stem cells (hESCs) to cardiomyocytes (CMs). We employed computational methodologies to predict target genes of both miR-200c and five key cardiac TFs to identify co-regulated gene networks. The inferred cardiac networks revealed that the cooperative action of miR-200c with these five key TFs, including three (GATA4, SRF and TBX5) targeted by miR-200c, should modulate key processes and pathways necessary for CM development and function. Experimentally, over-expression (OE) of miR-200c in hESC-CMs reduced the mRNA levels of GATA4, SRF and TBX5. Cardiac expression of Ca2+, K+ and Na+ ion channel genes (CACNA1C, KCNJ2 and SCN5A) were also significantly altered by knockdown or OE of miR-200c. Luciferase reporter assays validated miR-200c binding sites on the 3′ untranslated region of CACNA1C. In hESC-CMs, elevated miR-200c increased beating frequency, and repressed both Ca2+ influx, mediated by the L-type Ca2+ channel and Ca2+ transients. Conclusions Our analyses demonstrate that miR-200c represses hESC-CM differentiation and maturation. The integrative computation and experimental approaches described here, when applied more broadly, will enhance our understanding of the interplays between miRNAs and TFs in controlling cardiac development and disease processes.
Persistent Identifierhttp://hdl.handle.net/10722/261256
ISSN
2017 Impact Factor: 6.29
2015 SCImago Journal Rankings: 2.897
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorPoon, NYE-
dc.contributor.authorHao, B-
dc.contributor.authorGuan, D-
dc.contributor.authorLi, J-
dc.contributor.authorLu, J-
dc.contributor.authorYang, Y-
dc.contributor.authorWu, B-
dc.contributor.authorWu, CM-
dc.contributor.authorWebb, SE-
dc.contributor.authorLiang, Y-
dc.contributor.authorMiller, AL-
dc.contributor.authorYao, X-
dc.contributor.authorWang, J-
dc.contributor.authorYan, B-
dc.contributor.authorBoheler, KR-
dc.date.accessioned2018-09-14T08:55:11Z-
dc.date.available2018-09-14T08:55:11Z-
dc.date.issued2018-
dc.identifier.citationCardiovascular Research, 2018, v. 114 n. 6, p. 894-906-
dc.identifier.issn0008-6363-
dc.identifier.urihttp://hdl.handle.net/10722/261256-
dc.description.abstractAims MicroRNAs (miRNAs) are crucial for the post-transcriptional control of protein-encoding genes and together with transcription factors (TFs) regulate gene expression; however, the regulatory activities of miRNAs during cardiac development are only partially understood. In this study, we tested the hypothesis that integrative computational approaches could identify miRNAs that experimentally could be shown to regulate cardiomyogenesis. Methods and results We integrated expression profiles with bioinformatics analyses of miRNA and TF regulatory programs to identify candidate miRNAs involved with cardiac development. Expression profiling showed that miR-200c, which is not normally detected in adult heart, is progressively down-regulated both during cardiac development and in vitro differentiation of human embryonic stem cells (hESCs) to cardiomyocytes (CMs). We employed computational methodologies to predict target genes of both miR-200c and five key cardiac TFs to identify co-regulated gene networks. The inferred cardiac networks revealed that the cooperative action of miR-200c with these five key TFs, including three (GATA4, SRF and TBX5) targeted by miR-200c, should modulate key processes and pathways necessary for CM development and function. Experimentally, over-expression (OE) of miR-200c in hESC-CMs reduced the mRNA levels of GATA4, SRF and TBX5. Cardiac expression of Ca2+, K+ and Na+ ion channel genes (CACNA1C, KCNJ2 and SCN5A) were also significantly altered by knockdown or OE of miR-200c. Luciferase reporter assays validated miR-200c binding sites on the 3′ untranslated region of CACNA1C. In hESC-CMs, elevated miR-200c increased beating frequency, and repressed both Ca2+ influx, mediated by the L-type Ca2+ channel and Ca2+ transients. Conclusions Our analyses demonstrate that miR-200c represses hESC-CM differentiation and maturation. The integrative computation and experimental approaches described here, when applied more broadly, will enhance our understanding of the interplays between miRNAs and TFs in controlling cardiac development and disease processes.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://cardiovascres.oxfordjournals.org-
dc.relation.ispartofCardiovascular Research-
dc.subjectBioinformatics methods-
dc.subjectGene regulatory network-
dc.subjectmiRNA-200c-
dc.subjectPluripotent stem cell-derived cardiomyocyte differentiation and maturation-
dc.subjectTranscription factor-
dc.titleIntegrated transcriptomics and regulatory network analyses identify microRNA-200c as a novel repressor of differentiation and maturation of human pluripotent stem cell-derived cardiomyocytes-
dc.typeArticle-
dc.identifier.emailPoon, NYE: ellpoon@hku.hk-
dc.identifier.emailLi, J: mulin@hku.hk-
dc.identifier.emailYan, B: yanbin14@hku.hk-
dc.identifier.emailBoheler, KR: bohelerk@HKUCC-COM.hku.hk-
dc.identifier.authorityPoon, NYE=rp02233-
dc.identifier.authorityYan, B=rp01940-
dc.identifier.authorityBoheler, KR=rp01884-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1093/cvr/cvy019-
dc.identifier.scopuseid_2-s2.0-85047108776-
dc.identifier.hkuros290459-
dc.identifier.volume114-
dc.identifier.issue6-
dc.identifier.spage894-
dc.identifier.epage906-
dc.identifier.isiWOS:000432181500021-
dc.publisher.placeUnited Kingdom-

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