title: Integrative Analysis of the Developing Postnatal Mouse Heart Transcriptome.
abstract: In mammals, cardiomyocytes rapidly proliferate in the fetus and continue to do so for a few more days after birth. These cardiomyocytes then enter into growth arrest but the detailed molecular mechanisms involved have not been fully elucidated. We have addressed this issue by comparing the transcriptomes of 2-day-old (containing dividing cardiomyocytes) with 13-day-old (containing growth arrested cardiomyocytes) postnatal mouse hearts. We performed comparative microarray analysis on the heart tissues and then conducted Functional annotation, Gene ontology, KEGG pathway and Gene Set enrichment analyses on the differentially expressed genes. The bioinformatics analysis revealed that gene ontology categories associated with the "cell cycle", "DNA replication", "chromosome segregation" and "microtubule cytoskeleton" were down-regulated. Inversely, "immune response", "extracellular matrix", "cell differentiation" and "cell membrane" were up-regulated. Ingenuity Pathways Analysis (IPA) has revealed that GATA4, MYH7 and IGF1R were the key drivers of the gene interaction networks. In addition, Regulator Effects network analysis suggested that TASP1, TOB1, C1orf61, AIF1, ROCK1, TFF2 and miR503-5p may be acting on the cardiomyocytes in 13-day-old mouse hearts to inhibit cardiomyocyte proliferation and G1/S phase transition. RT-qPCR was used to validate genes which were differentially expressed and genes that play a prominent role in the pathways and interaction networks that we identified. In sum, our integrative analysis has provided more insights into the transcriptional regulation of cardiomyocyte exit from the cell cycle during postnatal heart development. The results also pinpoint potential regulators that could be used to induce growth arrested cardiomyocytes to proliferate in the infarcted heart.
authors.affiliation: Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Hong Kong.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Gan
authors.affiliation: Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Sonntag
authors.affiliation: Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Hong Kong.
authors.forename: Mei Kuen
authors.initials: MK
authors.lastname: Tang
authors.affiliation: Key Laboratory for Regenerative Medicine, Ministry of Education, Ji Nan University, Guangzhou, 510632, China.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Cai
authors.affiliation: Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin, N.T., Hong Kong, Hong Kong; Key Laboratory for Regenerative Medicine, Ministry of Education, Ji Nan University, Guangzhou, 510632, China.
authors.forename: Kenneth Ka Ho
authors.initials: KK
authors.lastname: Lee
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000502:physiology*; D006321:Heart / Q000254:growth & development*; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D059467:Transcriptome / Q000502:physiology*; D000071164:Trefoil Factor-2
chemical_list: D009124:Muscle Proteins; C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2