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

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. Flavell, Jeannie T. Lee, Chiara Gerhardinger, Amy J. Wagers and John L. Rinn ()
Additional contact information
Jordan P. Lewandowski: Harvard University
James C. Lee: Harvard University
Taeyoung Hwang: Harvard University
Hongjae Sunwoo: Massachusetts General Hospital
Jill M. Goldstein: Harvard University
Abigail F. Groff: Harvard University
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
Chiara Gerhardinger: Harvard University
Amy J. Wagers: Harvard University
John L. Rinn: Harvard University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12970-4

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