Kirino Research

The overarching goal of the Kirino lab is to decode how short non-coding RNAs (sncRNAs) are generated, how they signal within and between cells, and how this hidden layer of the transcriptome can be exploited for diagnostics and therapeutics. We focus on tRNA-derived sncRNAs (particularly tRNA halves) and 2′,3′-cyclic phosphate-containing RNAs (cP-RNAs) as pivotal regulators at the crossroads of gene expression, stress responses, and innate immunity, and we also investigate Piwi-interacting RNAs (piRNAs) in germline development and genome defense. By integrating RNA biology/biochemistry, molecular and cellular biology, and sequencing/computational approaches, the lab aims to translate fundamental RNA biology into next-generation biomarkers and RNA-targeted therapies in cancer, infection, inflammatory lung disease, and neuropsychiatric disorders.

Yohei Kirino, PhD, is a Professor in the Computational Medicine Center and in Department of Biochemistry and Molecular Biology at Thomas Jefferson University, which he joined in 2013. Before coming to Jefferson, he served as an Assistant Professor in the Department of Biomedical Sciences at Cedars-Sinai Medical Center. Dr. Kirino received his BSc (2001), MSc (2003), and PhD (2006) from The University of Tokyo in the laboratory of Dr. Tsutomu Suzuki, and completed his postdoctoral training (2006–2010) in the laboratory of Dr. Zissimos Mourelatos at the University of Pennsylvania School of Medicine.

Standard RNA-seq misses many structured/heavily modified sncRNAs (Reviewed in Front Genet 2018; Biomolecules 2022). The lab develops sequencing and quantitative platforms to reveal this hidden layer of the transcriptome and to enable sncRNA-based biomarker discovery. We established cP-RNA-seq to specifically profile cP-RNAs (including 5′ tRNA halves) (PNAS 2015; Nat Protoc 2016; Methods Enzymol 2025a) and used it to generate genome-wide maps of short cP-RNAs (PLoS Genet 2019; Biosci Biotechnol Biochem 2025) and to reveal their regulation by hormones (PNAS 2015), immune activation (PLoS Biol 2020), aging (PLoS Genet 2019), and cellular stress (RNA 2020). We also developed YAMAT-seq for efficient high-throughput sequencing of mature tRNAs (Nucleic Acids Res 2017), uncovering previously unrecognized mitochondrial sncRNAs with CCA-added 3′-termini (RNA Biol 2019). For precise quantification, we created Dumbbell-PCR (Nucleic Acids Res 2015; Methods Mol Biol 2018), Four-Leaf Clover RT-qPCR (RNA Biol 2015), and TaqMan RT-qPCR (PNAS 2015; Methods 2022; Methods Enzymol 2025b) to measure individual sncRNA variants, including clinically relevant tRNA halves, in cells and clinical samples. Together, these tools allow us to profile otherwise hidden sncRNAs in cells and biofluids, define disease-specific signatures of sncRNAs, and position these circulating sncRNAs as liquid-biopsy biomarkers.

The lab has identified sex hormone-dependent tRNA halves that are abundantly expressed in hormone-dependent breast and prostate cancers (PNAS 2015; Mol Cell Oncol 2016; RNA 2017). Generated by angiogenin-catalyzed anticodon cleavage, these tRNA halves actively promote tumor cell proliferation (PLoS Biol 2025), revealing a tRNA half-driven pathway in tumorigenesis and positioning them as candidate biomarkers and RNA-based targets in hormone-dependent malignancies.

The lab has uncovered disease-induced tRNA halves that function as potent innate immune ligands. We identified infection-induced tRNA halves in human macrophages that are selectively packaged into extracellular vesicles and activate endosomal Toll-like receptor 7 (TLR7) (PLoS Biol 2020; PNAS 2024), with marked upregulation in plasma from patients with Mycobacterium tuberculosis infection (Methods 2022; Mol Ther Nucleic Acids 2024a). We further showed that specific tRNA halves elevated in chronic obstructive pulmonary disease (COPD) plasma activate human macrophages via TLR7 and induce cytokine production, establishing circulating tRNA halves as immune mediators in chronic lung disease (Mol Ther Nucleic Acids 2024b). Ongoing and collaborative work extends these studies to eosinophil-derived neurotoxin (RNase 2/EDN)-mediated production of tRNA halves in asthma (bioRxiv 2025) and to dysregulated tRNA halves in schizophrenia (J Clin Invest 2026). Together, these findings define tRNA halves as a previously unrecognized class of endogenous immunostimulants and position them as promising targets and tools for next-generation RNA-based therapies.

In animal germlines, Piwi proteins and the associated piRNAs protect genome integrity by silencing transposons. We have utilized mouse, Bombyx, and Drosophila systems to elucidate the biogenesis mechanism of piRNAs (Nat Struct Mol Biol 2007; RNA 2007; Nat Cell Biol 2009; RNA 2010; J Biol Chem 2010; Cell 2016; Sci Rep 2017; Nucleic Acids Res 2017). The lab has identified key factors in this pathway, including the Tudor-domain protein BmPapi (RNA 2013), which scaffolds piRNA maturation on mitochondria, and the mitochondria-associated endoribonuclease RNase K, which produces cP-RNAs as direct piRNA precursors and thereby establishes cP-RNAs as central intermediates linking RNA metabolism, piRNA biogenesis, and germline development (Nat Commun 2021).