Abstract 2302: Systematic and Comparative Analyses of Gene Expression in Cardiac Development and Hypertrophy Reveal Common and Distinct Transcriptional and Post-transcriptional Gene Regulatory Modules
We are interested in understanding gene regulatory programs under different growth conditions of the heart. We first took a bioinformatics approach to analyze gene expression profiles at different stages of embryonic heart development (E12.5-E18.5, n=3 for each group), neonatal heart development (1, 20, 49 days after birth, n=3 for each group), and adult cardiac hypertrophy induced by transverse aortic constriction (TAC). For hypertrophy, we used multiple microarray data sets from different laboratories including ours to enhance the reliability of our study (5 datasets having 1, 2, 4, 12week TAC). Clustering analysis of gene expression and analysis of gene sets, such as Gene Ontology (GO) groups, indicated common and distinct regulatory modules for these 3 stages of heart growth. Consistent with the well-known ‘fetal gene program’, many genes and pathways showed opposite regulation in hypertrophy compared with embryonic and neonatal growth, with most significant genes involved in mitochondrial functions, extracellular matrix, cytoskeleton, and cell cycle (p < 0.001, hypergeometric test). By examining the promoter regions of regulated genes and the 3′ untranslated regions of mRNAs, we predicted a number of transcription factor-mediated regulatory modules and microRNA-medicated regulatory modules, respectively. Some of these have been previously reported (E2F, SRF, miR-1, miR-29, etc.) and others appear to be novel. Interestingly, a number of mRNA processing genes are highly regulated in both early development and hypertrophy, suggesting regulation of mRNA processing. Using the whole genome exon array, we found widespread regulation of mRNA isoforms (> 30% change in exon inclusion/exclusion) due to alternative splicing and/or polyadenylation in hypertrophy, many of which are also regulated in early development. We predicted functional cis elements that are involved in the regulations of alternative mRNA processing (p < 0.01, Fisher’s exact test). Thus, our results indicate that many gene regulatory modules functioning at transcriptional and post-transcriptional levels are commonly and distinctly implemented under different conditions of heart growth.