Identification of human pathways acting on nuclear non-coding RNAs using the Mirror forward genetic approach

Rui Che, Monireh Panah, Bhoomi Mirani, Krista Knowles, Anastacia Ostapovich, Debarati Majumdar, Xiaotong Chen, Joseph DeSimone, William White, Megan Noonan, Hong Luo and Andrei Alexandrov ()
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Rui Che: Clemson University
Monireh Panah: Clemson University
Bhoomi Mirani: Clemson University
Krista Knowles: Clemson University
Anastacia Ostapovich: Yale University
Debarati Majumdar: Clemson University
Xiaotong Chen: Clemson University
Joseph DeSimone: Clemson University
William White: Clemson University
Megan Noonan: Clemson University
Hong Luo: Clemson University
Andrei Alexandrov: Clemson University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Despite critical roles in diseases, human pathways acting on strictly nuclear non-coding RNAs have been refractory to forward genetics. To enable their forward genetic discovery, we developed a single-cell approach that “Mirrors” activities of nuclear pathways with cytoplasmic fluorescence. Application of Mirror to two nuclear pathways targeting MALAT1’s 3′ end, the pathway of its maturation and the other, the degradation pathway blocked by the triple-helical Element for Nuclear Expression (ENE), identified nearly all components of three complexes: Ribonuclease P and the RNA Exosome, including nuclear DIS3, EXOSC10, and C1D, as well as the Nuclear Exosome Targeting (NEXT) complex. Additionally, Mirror identified DEAD-box helicase DDX59 associated with the genetic disorder Oral-Facial-Digital syndrome (OFD), yet lacking known substrates or roles in nuclear RNA degradation. Knockout of DDX59 exhibits stabilization of the full-length MALAT1 with a stability-compromised ENE and increases levels of 3′-extended forms of small nuclear RNAs. It also exhibits extensive retention of minor introns, including in OFD-associated genes, suggesting a mechanism for DDX59 association with OFD. Mirror efficiently identifies pathways acting on strictly nuclear non-coding RNAs, including essential and indirectly-acting components, and as a result can uncover unexpected links to human disease.

Date: 2025
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DOI: 10.1038/s41467-025-59998-3

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