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. 2014 Aug 19;111(33):12264-9.
doi: 10.1073/pnas.1410622111. Epub 2014 Jul 28.

"VSports app下载" Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs

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Epigenetic coordination of embryonic heart transcription by dynamically regulated long noncoding RNAs

Scot J Matkovich et al. Proc Natl Acad Sci U S A. .

V体育官网入口 - Abstract

The vast majority of mammalian DNA does not encode for proteins but instead is transcribed into noncoding (nc)RNAs having diverse regulatory functions. The poorly characterized subclass of long ncRNAs (lncRNAs) can epigenetically regulate protein-coding genes by interacting locally in cis or distally in trans. A few reports have implicated specific lncRNAs in cardiac development or failure, but precise details of lncRNAs expressed in hearts and how their expression may be altered during embryonic heart development or by adult heart disease is unknown. Using comprehensive quantitative RNA sequencing data from mouse hearts, livers, and skin cells, we identified 321 lncRNAs present in the heart, 117 of which exhibit a cardiac-enriched pattern of expression. By comparing lncRNA profiles of normal embryonic (∼E14), normal adult, and hypertrophied adult hearts, we defined a distinct fetal lncRNA abundance signature that includes 157 lncRNAs differentially expressed compared with adults (fold-change ≥ 50%, false discovery rate = 0. 02) and that was only poorly recapitulated in hypertrophied hearts (17 differentially expressed lncRNAs; 13 of these observed in embryonic hearts). Analysis of protein-coding mRNAs from the same samples identified 22 concordantly and 11 reciprocally regulated mRNAs within 10 kb of dynamically expressed lncRNAs, and reciprocal relationships of lncRNA and mRNA levels were validated for the Mccc1 and Relb genes using in vitro lncRNA knockdown in C2C12 cells. Network analysis suggested a central role for lncRNAs in modulating NFκB- and CREB1-regulated genes during embryonic heart growth and identified multiple mRNAs within these pathways that are also regulated, but independently of lncRNAs. VSports手机版.

Keywords: fetal heart; pressure overload. V体育安卓版.

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VSports - Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Tissue selective patterns of mouse lncRNA expression. (A) Principal components analyses of n = 25 adult mouse hearts, n = 7 adult mouse livers, and n = 6 cultured mouse keratinocytes (skin). (B) Heat map display for unsupervised hierarchical clustering of fold-change in expression between the three mouse tissues [reads per million lncRNA aligned reads (RPM)]. (C) Venn diagram revealing patterns of tissue-selective lncRNAs expressed at >0.3 RPKM (reads per kilobase of RNA length per million reads mapped to all transcribed RNA, where all transcribed RNA comprises reads mapped to mRNAs and 2,140 defined lncRNAs).
Fig. 2.
Fig. 2.
lncRNA expression is regulated during embryonic development but not after TAC. (A–C) Unsupervised cluster analysis of normal adult and ∼E14 C57BL/6 embryonic heart lncRNA expression. (A) Three hundred twenty-one lncRNAs expressed >0.3 RPKM in hearts. (B) Fifty-two cardiac-selective abundant (>1 RPKM) lncRNAs. (C) One hundred five non–cardiac-selective abundant lncRNAs. (D–F) Same lncRNAs as displayed in AC, showing data from sham-operated vs. pressure overloaded (TAC) adult hearts, 1 wk, and 4 wk.
Fig. 3.
Fig. 3.
Comparison of embryonic and pressure overload heart lncRNA and mRNA signatures. (A) Unsupervised cluster analysis for 17 abundant lncRNAs regulated after 1 or 4 wk TAC. *Opposite regulation by TAC vs. embryonic state; +regulated by TAC only, not by embryonic state. (B) Analysis of fetal gene mRNA expression in the same embryonic (E), adult (A), sham (S), and 1- and 4-wk TAC hearts (1, 4). (C and D) Combined lncRNA analysis across the four study groups; pressure overload responses are shown only for the 4-wk time point. (C) Principal components analysis. (D) Standardized lncRNA expression (fold-change). (E and F) Same as C and D for mRNA expression. Venn diagrams to the right show patterns of overlap between fetal- and TAC-regulated lncRNAs (Upper) and mRNAs (Lower).
Fig. 4.
Fig. 4.
Expression of 10-kb lncRNA-mRNA partners. (A) Heat map of standardized (fold-change) expression for 33 coregulated lncRNA-mRNA pairs. lncRNA/mRNA is indicated at the top. Asterisks show instances of nonconcordant regulation. (B) Quantitative expression of the nonconcordantly regulated lncRNA/mRNA pair n413804/Kcnq1 (black is lncRNA; red is mRNA).
Fig. 5.
Fig. 5.
Nonconcordantly regulated 10-kb lncRNA-mRNA partners in embryonic hearts. (A) (Left) Quantitative expression of the nonconcordantly regulated lncRNA/mRNA pair n411949/Mccc1 (black is lncRNA; red is mRNA) in embryonic and adult hearts; expression in sham and 4-wk TAC hearts is shown for comparison (differences with TAC do not meet significance criteria). (Right) Relative positions of lncRNA n411949 and mRNA Mccc1 within the genome; other transcripts within the locus are colored blue. (B) (Left) Positions targeted by anti-lncRNA gapmers, and primer design for lncRNA (arrows) and mRNA (arrows + internal probe) qPCR detection. (Right) lncRNA and mRNA expression in C2C12 cells transfected with anti-lncRNA gapmers, relative to geometric mean of Actb, Gapdh, and Hmbs (mean ± SEM, n = 6; representative of at least two independent experiments). Non, nontransfected cells; Neg, transfected with fluorescein amidite (FAM)-labeled control gapmer; gapmeR-1 and -2, transfected with one of two different gapmeRs against the chosen lncRNA. *P < 0.05 relative to negative control (Neg). (C and D) Same as A and B, but for the nonconcordantly regulated lncRNA/mRNA pair n413445/Relb.
Fig. 6.
Fig. 6.
Signaling networks of mRNAs involved in lncRNA-mRNA relationships. MetaCore analysis of functional networks involving regulated cardiac mRNAs linked to regulated cardiac lncRNAs. Green arrows, up-regulation; red arrows, down-regulation; gray lines, context-dependent interaction. Blue circles are mRNAs directly linked to regulated lncRNAs, green circles are mRNAs also regulated, but not connected to lncRNAs described in our study. Note central nodes for NFκB and CREB1.

References (VSports在线直播)

    1. Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148(6):1172–1187. - PMC - PubMed
    1. Batista PJ, Chang HY. Long noncoding RNAs: Cellular address codes in development and disease. Cell. 2013;152(6):1298–1307. - PMC - PubMed
    1. Klattenhoff CA, et al. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 2013;152(3):570–583. - PMC - PubMed
    1. Grote P, et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell. 2013;24(2):206–214. - PMC - PubMed
    1. Lee JH, et al. Analysis of transcriptome complexity through RNA sequencing in normal and failing murine hearts. Circ Res. 2011;109(12):1332–1341. - PMC - PubMed

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