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Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules.

Park JY, Li W, Zheng D, Zhai P, Zhao Y, Matsuda T, Vatner SF, Sadoshima J, Tian B - PLoS ONE (2011)

Bottom Line: 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".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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America.

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.

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Comparison of mRNA isoform regulation in cardiac hypertrophy and development.(A) Comparison of SI for skipped exons (SE). Skipped exons were defined by cDNAs/ESTs. Grey dots are all expressed SE events, and blue dots are the ones that are developmentally regulated and experimentally validated in a previous study [25]. The dotted red line is based on linear regression of blue dots. Pearson correlation coefficient was calculated for each plot, and its E value was estimated based on random sampling of the same number of exons (see Materials and Methods for detail). (B) Venn diagram showing the highly regulated SEs in hypertrophy and development. Highly regulated SEs were selected using 1*SD of SI. (C) and (D) Regulation of alternative first and last exons. U and D are upstream and downstream terminal exons, respectively. Alternative terminal exons were analyzed using difference in log2(U/D) or log2(D/U), where U/D or D/U are ratios of probe set intensities between U and D.
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pone-0022391-g003: Comparison of mRNA isoform regulation in cardiac hypertrophy and development.(A) Comparison of SI for skipped exons (SE). Skipped exons were defined by cDNAs/ESTs. Grey dots are all expressed SE events, and blue dots are the ones that are developmentally regulated and experimentally validated in a previous study [25]. The dotted red line is based on linear regression of blue dots. Pearson correlation coefficient was calculated for each plot, and its E value was estimated based on random sampling of the same number of exons (see Materials and Methods for detail). (B) Venn diagram showing the highly regulated SEs in hypertrophy and development. Highly regulated SEs were selected using 1*SD of SI. (C) and (D) Regulation of alternative first and last exons. U and D are upstream and downstream terminal exons, respectively. Alternative terminal exons were analyzed using difference in log2(U/D) or log2(D/U), where U/D or D/U are ratios of probe set intensities between U and D.

Mentions: We next asked how the isoform regulation in hypertrophy was related to that in development. To this end, we compared exon usage changes in hypertrophy using our exon array data and those in development using the splicing microarray data (EA) [25]. We focused on three types of isoform changes, namely skipping of internal exon (SE), alternative first exon (AFE), and alternative last exon (ALE) (Figure 3).


Comparative analysis of mRNA isoform expression in cardiac hypertrophy and development reveals multiple post-transcriptional regulatory modules.

Park JY, Li W, Zheng D, Zhai P, Zhao Y, Matsuda T, Vatner SF, Sadoshima J, Tian B - PLoS ONE (2011)

Comparison of mRNA isoform regulation in cardiac hypertrophy and development.(A) Comparison of SI for skipped exons (SE). Skipped exons were defined by cDNAs/ESTs. Grey dots are all expressed SE events, and blue dots are the ones that are developmentally regulated and experimentally validated in a previous study [25]. The dotted red line is based on linear regression of blue dots. Pearson correlation coefficient was calculated for each plot, and its E value was estimated based on random sampling of the same number of exons (see Materials and Methods for detail). (B) Venn diagram showing the highly regulated SEs in hypertrophy and development. Highly regulated SEs were selected using 1*SD of SI. (C) and (D) Regulation of alternative first and last exons. U and D are upstream and downstream terminal exons, respectively. Alternative terminal exons were analyzed using difference in log2(U/D) or log2(D/U), where U/D or D/U are ratios of probe set intensities between U and D.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3142162&req=5

pone-0022391-g003: Comparison of mRNA isoform regulation in cardiac hypertrophy and development.(A) Comparison of SI for skipped exons (SE). Skipped exons were defined by cDNAs/ESTs. Grey dots are all expressed SE events, and blue dots are the ones that are developmentally regulated and experimentally validated in a previous study [25]. The dotted red line is based on linear regression of blue dots. Pearson correlation coefficient was calculated for each plot, and its E value was estimated based on random sampling of the same number of exons (see Materials and Methods for detail). (B) Venn diagram showing the highly regulated SEs in hypertrophy and development. Highly regulated SEs were selected using 1*SD of SI. (C) and (D) Regulation of alternative first and last exons. U and D are upstream and downstream terminal exons, respectively. Alternative terminal exons were analyzed using difference in log2(U/D) or log2(D/U), where U/D or D/U are ratios of probe set intensities between U and D.
Mentions: We next asked how the isoform regulation in hypertrophy was related to that in development. To this end, we compared exon usage changes in hypertrophy using our exon array data and those in development using the splicing microarray data (EA) [25]. We focused on three types of isoform changes, namely skipping of internal exon (SE), alternative first exon (AFE), and alternative last exon (ALE) (Figure 3).

Bottom Line: 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".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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States of America.

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.

Show MeSH
Related in: MedlinePlus