期刊
EMBO JOURNAL
卷 38, 期 11, 页码 -出版社
WILEY
DOI: 10.15252/embj.2019101695
关键词
cell-free RNA; extracellular RNA; liquid biopsy; RNA-seq
资金
- NIH Extracellular RNA Communication Common Fund grants: U01 grants [HL126499, HL126496]
- A. Alfred Taubman Medical Research Institute (Grand Challenge Award)
- National Cancer Institute of the NIH [P30CA046592]
- Precision Health Scholar Award from the University of Michigan Precision Health Center
- Spanish Institute of Health Carlos III from the Ministry of Economy and Competitiveness (European Social Fund (ESF)) [JR18/00026]
- Pacific Northwest Research Institute
Extracellular RNAs (exRNAs) in biofluids have attracted great interest as potential biomarkers. Although extracellular microRNAs in blood plasma are extensively characterized, extracellular messenger RNA (mRNA) and long non-coding RNA (lncRNA) studies are limited. We report that plasma contains fragmented mRNAs and lncRNAs that are missed by standard small RNA-seq protocols due to lack of 5 ' phosphate or presence of 3 ' phosphate. These fragments were revealed using a modified protocol (phospho-RNA-seq) incorporating RNA treatment with T4-polynucleotide kinase, which we compared with standard small RNA-seq for sequencing synthetic RNAs with varied 5 ' and 3 ' ends, as well as human plasma exRNA. Analyzing phospho-RNA-seq data using a custom, high-stringency bioinformatic pipeline, we identified mRNA/lncRNA transcriptome fingerprints in plasma, including tissue-specific gene sets. In a longitudinal study of hematopoietic stem cell transplant patients, bone marrow- and liver-enriched exRNA genes were tracked with bone marrow recovery and liver injury, respectively, providing proof-of-concept validation as a biomarker approach. By enabling access to an unexplored realm of mRNA and lncRNA fragments, phospho-RNA-seq opens up new possibilities for plasma transcriptomic biomarker development.
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