Abstract
One promising goal for utilizing the molecular information circulating in biofluids is the discovery of clinically useful biomarkers. Extracellular RNAs (exRNAs) are one of the most diverse classes of molecular cargo, easily assayed by sequencing and with expressions that rapidly change in response to subject status. Despite diverse exRNA cargo, most evaluations from biofluids have focused on small RNA sequencing and analysis, specifically on microRNAs (miRNAs). Another goal of characterizing circulating molecular information, is to correlate expression to injuries associated with specific tissues of origin. Biomarker candidates are often described as being specific, enriched in a particular tissue or associated with a disease process. Likewise, miRNA data is often reported to be specific, enriched for a tissue, without rigorous testing to support the claim. Here we provide a tissue atlas of small RNAs from 30 different tissues and three different blood cell types. We analyzed the tissues for enrichment of small RNA sequences and assessed their expression in biofluids: plasma, cerebrospinal fluid, urine, and saliva. We employed published data sets representing physiological (resting vs. acute exercise) and pathologic states (early- vs. late-stage liver fibrosis, and differential subtypes of stroke) to determine differential tissue-enriched small RNAs. We also developed an online tool that provides information about exRNA sequences found in different biofluids and tissues. The data can be used to better understand the various types of small RNA sequences in different tissues as well as their potential release into biofluids, which should help in the validation or design of biomarker studies.
Highlights
Extracellular RNAs have been identified in every biofluid tested to-date (Yáñez-Mó et al, 2015; Yeri et al, 2017; Murillo et al, 2019; Srinivasan et al, 2019; Hulstaert et al, 2020) and are found within extracellular vesicles (EVs) and associated with RNA binding proteins or lipoprotein particles (Valadi et al, 2007; Skog et al, 2008; Arroyo et al, 2011; Turchinovich et al, 2011; Tabet et al, 2014)
We included 37 cerebrospinal fluid (CSF) and 35 matched plasma samples isolated with exoRNeasy to enrich for Extracellular RNAs (exRNAs) contained in EVs
We show that plasma and urine samples show the highest mapping rates to the human genome, while saliva and CSF samples have lower mapping rates (Figure 1A)
Summary
Extracellular RNAs (exRNAs) have been identified in every biofluid tested to-date (Yáñez-Mó et al, 2015; Yeri et al, 2017; Murillo et al, 2019; Srinivasan et al, 2019; Hulstaert et al, 2020) and are found within extracellular vesicles (EVs) and associated with RNA binding proteins or lipoprotein particles (Valadi et al, 2007; Skog et al, 2008; Arroyo et al, 2011; Turchinovich et al, 2011; Tabet et al, 2014). While longer RNAs (>200 nucleotides) can be detected in biofluids (Wei et al, 2017; Everaert et al, 2019; Hulstaert et al, 2020; Rodosthenous et al, 2020), most studies have focused on small RNA biotypes (
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