{"doi":"10.1101/2021.04.30.442191","title":"In heart failure reactivation of RNA-binding proteins drives the transcriptome into a fetal state","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218690,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9457,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":295856,"name":"Jennifer Nguyen","orcid":"0000-0001-7019-0311","position":1,"is_corresponding":false},{"id":225252,"name":"Timothy D. Arthur","orcid":"0000-0002-3393-1691","position":2,"is_corresponding":false},{"id":265331,"name":"Hiroko Matsui","orcid":null,"position":3,"is_corresponding":false},{"id":263536,"name":"Margaret K. R. Donovan","orcid":"0000-0001-5240-4216","position":4,"is_corresponding":false},{"id":263542,"name":"Agnieszka D’Antonio‐Chronowska","orcid":"0000-0003-1653-4106","position":5,"is_corresponding":false},{"id":95977,"name":"Kelly A. Frazer","orcid":"0000-0002-6060-8902","position":6,"is_corresponding":false},{"id":263535,"name":"Matteo D’Antonio","orcid":"0000-0001-5844-6433","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:29.626149Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}