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bioRxiv · 10.1101/2021.04.30.442191

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

D'Antonio, M.·Nguyen, J. P.·Arthur, T. D.·Matsui, H.·Donovan, M. K. R.·DAntonio-Chronowska, A.·Frazer, K. A.
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Abstract

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.

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D'Antonio, M., Nguyen, J. P., Arthur, T. D., Matsui, H., Donovan, M. K. R., DAntonio-Chronowska, A., Frazer, K. A.. 2021-05-01. In heart failure reactivation of RNA-binding proteins drives the transcriptome into a fetal state. https://doi.org/10.1101/2021.04.30.442191

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