title: Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules.
abstract: Cardiac hypertrophy is enlargement of the heart in response to physiological or pathological stimuli, chiefly involving growth of myocytes in size rather than in number. Previous studies have shown that the expression pattern of a group of genes in hypertrophied heart induced by pressure overload resembles that at the embryonic stage of heart development, a phenomenon known as activation of the "fetal gene program". Here, using a genome-wide approach we systematically defined genes and pathways regulated in short- and long-term cardiac hypertrophy conditions using mice with transverse aortic constriction (TAC), and compared them with those regulated at different stages of embryonic and postnatal development. In addition, exon-level analysis revealed widespread mRNA isoform changes during cardiac hypertrophy resulting from alternative usage of terminal or internal exons, some of which are also developmentally regulated and may be attributable to decreased expression of Fox-1 protein in cardiac hypertrophy. Genes with functions in certain pathways, such as cell adhesion and cell morphology, are more likely to be regulated by alternative splicing. Moreover, we found 3'UTRs of mRNAs were generally shortened through alternative cleavage and polyadenylation in hypertrophy, and microRNA target genes were generally de-repressed, suggesting coordinated mechanisms to increase mRNA stability and protein production during hypertrophy. Taken together, our results comprehensively delineated gene and mRNA isoform regulation events in cardiac hypertrophy and revealed their relations to those in development, and suggested that modulation of mRNA isoform expression plays an importance role in heart remodeling under pressure overload.
authors.affiliation: Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Park
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.forename: Dinghai
authors.initials: D
authors.lastname: Zheng
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Takahisa
authors.initials: T
authors.lastname: Matsuda
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D005333:Fetus / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D023281:Genomics; D006321:Heart / Q000503:physiopathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D059368:RNA Isoforms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014661:Vasoconstriction
chemical_list: D020413:3' Untranslated Regions; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D059368:RNA Isoforms; D012333:RNA, Messenger