In heart failure reactivation of RNA-binding proteins drives the transcriptome into a fetal state

Transcriptome-wide expression changes occur during heart failure, including reactivation of fetal-specific isoforms. However, the underlying molecular mechanisms and the extent to which a fetal gene program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternati...

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Bibliographic Details
Published inbioRxiv
Main Authors D'antonio, Matteo, Nguyen, Jennifer P, Arthur, Timothy D, Matsui, Hiroko, Margaret Kr Donovan, Dantonio-Chronowska, Agnieszka, Frazer, Kelly A
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 01.05.2021
Subjects
Alternative splicing
Cardiovascular system
Congestive heart failure
Fetuses
Gene expression
Heart failure
Isoforms
Molecular modelling
Progenitor cells
Proteins
Ribonucleic acid
RNA
RNA-binding protein
Stem cells
Transcriptomes
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Summary:Transcriptome-wide expression changes occur during heart failure, including reactivation of fetal-specific isoforms. However, the underlying molecular mechanisms and the extent to which a fetal gene program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) in cardiovascular system (CVS) tissues between fetal and adult (healthy and diseased) stages have included both cellular heterogeneity across bulk RNA-seq samples and limited availability of fetal tissue for research. To overcome these limitations, we have deconvoluted the cellular compositions of 996 RNA-seq samples representing heart failure, healthy adult (heart and arteria), and fetal-like (iPSC-derived cardiovascular progenitor cells) CVS tissues. Comparison of the expression profiles revealed that RNA-binding proteins (RBPs) are highly overexpressed in fetal-like compared with healthy adult and are reactivated in heart failure, which results in expression of thousands fetal-specific isoforms. Of note, isoforms for 20 different RBPs were among those that reverted in heart failure to the fetal-like expression pattern. We determined that, compared with adult-specific isoforms, fetal-specific isoforms are more likely to bind RBPs, have canonical sequences at their splice sites and encode proteins with more functions. Our findings suggest targeting RBP fetal-specific isoforms could result in novel therapeutics for heart failure. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://figshare.com/s/b2e70a2ba3a4aac935d9
DOI:10.1101/2021.04.30.442191