exRNA-eCLIP intersection analysis reveals a map of extracellular RNA binding proteins and associated RNAs across major human biofluids and carriers

Emily L LaPlante; Alessandra Stürchler; Robert Fullem; David Chen; Anne C Starner; Emmanuel Esquivel; Eric Alsop; Andrew R Jackson; Ionita Ghiran; Getulio Pereira; Joel Rozowsky; Justin Chang; Mark B Gerstein; Roger P Alexander; Matthew E Roth; Jeffrey L Franklin; Robert J Coffey; Robert L Raffai; Isabelle M Mansuy; Stavros Stavrakis; Andrew J deMello; Louise C Laurent; Yi-Ting Wang; Chia-Feng Tsai; Tao Liu; Jennifer Jones; Kendall Van Keuren-Jensen; Eric Van Nostrand; Bogdan Mateescu; Aleksandar Milosavljevic

doi:10.1016/j.xgen.2023.100303

exRNA-eCLIP intersection analysis reveals a map of extracellular RNA binding proteins and associated RNAs across major human biofluids and carriers

Cell Genom. 2023 Apr 20;3(5):100303. doi: 10.1016/j.xgen.2023.100303. eCollection 2023 May 10.

Authors

Emily L LaPlante¹, Alessandra Stürchler^{2

3}, Robert Fullem^{1

4}, David Chen¹, Anne C Starner⁵, Emmanuel Esquivel^{1

4}, Eric Alsop⁶, Andrew R Jackson¹, Ionita Ghiran⁷, Getulio Pereira⁷, Joel Rozowsky⁸, Justin Chang⁸, Mark B Gerstein⁸, Roger P Alexander⁹, Matthew E Roth¹, Jeffrey L Franklin^{10

11}, Robert J Coffey^{10

11}, Robert L Raffai^{12

13}, Isabelle M Mansuy³, Stavros Stavrakis², Andrew J deMello², Louise C Laurent¹⁴, Yi-Ting Wang¹⁵, Chia-Feng Tsai¹⁵, Tao Liu¹⁵, Jennifer Jones¹⁶, Kendall Van Keuren-Jensen⁶, Eric Van Nostrand^{5

17}, Bogdan Mateescu^{2

3}, Aleksandar Milosavljevic^{1

4

18}

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
² Institute for Chemical and Bioengineering, ETH Zürich, 8093 Zürich, Switzerland.
³ Brain Research Institute, University of Zürich, 8057 Zürich, Switzerland.
⁴ Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Verna & Marrs McLean Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, TX 76706, USA.
⁶ Neurogenomics Division, TGen, Phoenix, AZ 85004, USA.
⁷ Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁸ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
⁹ Extracellular RNA Communication Consortium, Phoenix, AZ 85254, USA.
¹⁰ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹¹ Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37235, USA.
¹² Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA.
¹³ Division of Endovascular and Vascular Surgery, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁴ Department of Obstetrics, Gynecology, and Reproductive Sciences and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁵ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
¹⁶ Laboratory of Pathology Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
¹⁷ Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁸ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

Although the role of RNA binding proteins (RBPs) in extracellular RNA (exRNA) biology is well established, their exRNA cargo and distribution across biofluids are largely unknown. To address this gap, we extend the exRNA Atlas resource by mapping exRNAs carried by extracellular RBPs (exRBPs). This map was developed through an integrative analysis of ENCODE enhanced crosslinking and immunoprecipitation (eCLIP) data (150 RBPs) and human exRNA profiles (6,930 samples). Computational analysis and experimental validation identified exRBPs in plasma, serum, saliva, urine, cerebrospinal fluid, and cell-culture-conditioned medium. exRBPs carry exRNA transcripts from small non-coding RNA biotypes, including microRNA (miRNA), piRNA, tRNA, small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), Y RNA, and lncRNA, as well as protein-coding mRNA fragments. Computational deconvolution of exRBP RNA cargo reveals associations of exRBPs with extracellular vesicles, lipoproteins, and ribonucleoproteins across human biofluids. Overall, we mapped the distribution of exRBPs across human biofluids, presenting a resource for the community.

Keywords: NIH ERCC; RNA binding proteins; RNA footprint correlation; cell-free RNAs; cell-free biomarkers; eCLIP; exRNA carriers; human biofluids; liquid biopsies; public resource.