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.
Highlights
The growth of the heart in mammals takes place at embryonic and postnatal developmental stages, but it can be induced by physiological or pathological stimuli in the adult [1]
To systematically examine gene regulation in short- and longterm cardiac hypertrophy, we used genome-wide exon microarrays to analyze mRNAs expressed in mouse hypertrophied left ventricle (LVH) induced by 1 week (1 W) or 4 W Transverse Aortic Constriction (TAC)
Our result indicates that cardiac hypertrophy involves widespread mRNA isoform changes, and some of the events are oppositely regulated in development, especially for those regulated at the early stage of hypertrophy
Summary
The growth of the heart in mammals takes place at embryonic and postnatal developmental stages, but it can be induced by physiological or pathological stimuli in the adult [1]. While cardiac growth at early developmental stages mostly involves proliferation of cardiac myocytes, expansion of cell size is responsible for growth of the adult heart The latter is known as cardiac hypertrophy, which is a common component of many cardiac diseases. A group of genes with low expression in the adult but high expression in the embryo is reactivated in cardiac hypertrophy, a phenomenon widely known as activation of the ‘fetal gene program’ These genes typically play roles in metabolic and contractile functions of the heart [7,8], and are regulated by a set of transcription factors (TFs) which play roles in embryonic development, such as NFAT, NFkB, MEF2, GATA4, and SRF [9,10]. Recent studies have implicated regulation of several microRNAs (miRNAs) in hypertrophy, including miR-1, miR-133, and miR-208 [11,12,13]. miRNAs are small non-coding RNAs (,22 nucleotides) that cause mRNA degradation and/or inhibition of translation by binding to their target sites in mRNAs, mostly in the 39 untranslated region (39UTR) [14,15]. miRNAs have been increasingly found to play important roles in cardiac development and diseases [16,17,18,19]
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