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The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

Author

Listed:
  • Jordan P. Lewandowski

    (Harvard University)

  • James C. Lee

    (Harvard University
    University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital)

  • Taeyoung Hwang

    (Harvard University
    University of Colorado Boulder)

  • Hongjae Sunwoo

    (Massachusetts General Hospital)

  • Jill M. Goldstein

    (Harvard University
    Paul F. Glenn Center for the Biology of Aging, Harvard Medical School)

  • Abigail F. Groff

    (Harvard University
    Harvard Medical School)

  • Nydia P. Chang

    (Harvard University)

  • William Mallard

    (Harvard University)

  • Adam Williams

    (JAX Genomic Medicine)

  • Jorge Henao-Meija

    (Perelman School of Medicine University of Pennsylvania)

  • Richard A. Flavell

    (Yale University, School of Medicine)

  • Jeannie T. Lee

    (Massachusetts General Hospital
    Harvard Medical School
    Howard Hughes Medical Institute)

  • Chiara Gerhardinger

    (Harvard University)

  • Amy J. Wagers

    (Harvard University
    Paul F. Glenn Center for the Biology of Aging, Harvard Medical School
    Joslin Diabetes Center)

  • John L. Rinn

    (Harvard University
    University of Colorado Boulder)

Abstract

RNA has been classically known to play central roles in biology, including maintaining telomeres, protein synthesis, and in sex chromosome compensation. While thousands of long noncoding RNAs (lncRNAs) have been identified, attributing RNA-based roles to lncRNA loci requires assessing whether phenotype(s) could be due to DNA regulatory elements, transcription, or the lncRNA. Here, we use the conserved X chromosome lncRNA locus Firre, as a model to discriminate between DNA- and RNA-mediated effects in vivo. We demonstrate that (i) Firre mutant mice have cell-specific hematopoietic phenotypes, and (ii) upon exposure to lipopolysaccharide, mice overexpressing Firre exhibit increased levels of pro-inflammatory cytokines and impaired survival. (iii) Deletion of Firre does not result in changes in local gene expression, but rather in changes on autosomes that can be rescued by expression of transgenic Firre RNA. Together, our results provide genetic evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in hematopoiesis.

Suggested Citation

  • Jordan P. Lewandowski & James C. Lee & Taeyoung Hwang & Hongjae Sunwoo & Jill M. Goldstein & Abigail F. Groff & Nydia P. Chang & William Mallard & Adam Williams & Jorge Henao-Meija & Richard A. Flavel, 2019. "The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12970-4
    DOI: 10.1038/s41467-019-12970-4
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    Cited by:

    1. Christian Much & Erika L. Lasda & Isabela T. Pereira & Tenaya K. Vallery & Daniel Ramirez & Jordan P. Lewandowski & Robin D. Dowell & Michael J. Smallegan & John L. Rinn, 2024. "The temporal dynamics of lncRNA Firre-mediated epigenetic and transcriptional regulation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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