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.

Details

Title
The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis
Author
Lewandowski, Jordan P 1 ; Lee, James C 2   VIAFID ORCID Logo  ; Hwang, Taeyoung 3 ; Sunwoo, Hongjae 4   VIAFID ORCID Logo  ; Goldstein, Jill M 5 ; Groff, Abigail F 6 ; Chang, Nydia P 1 ; Mallard, William 1   VIAFID ORCID Logo  ; Williams, Adam 7 ; Henao-Meija, Jorge 8 ; Flavell, Richard A 9   VIAFID ORCID Logo  ; Lee, Jeannie T 10   VIAFID ORCID Logo  ; Gerhardinger, Chiara 1 ; Wagers, Amy J 11 ; Rinn, John L 3   VIAFID ORCID Logo 

1  Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA 
2  Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK 
3  Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA 
4  Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA 
5  Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA 
6  Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA 
7  The Jackson Laboratory, JAX Genomic Medicine, Farmington, CT, USA 
8  Department of Pathology and Laboratory Medicine, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA 
9  Department of Immunobiology and Howard Hughes Medical Institute, Yale University, School of Medicine, New Haven, CT, USA 
10  Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA 
11  Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, USA; Joslin Diabetes Center, Boston, MA, USA 
Pages
1-13
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-12970-4
ProQuest document ID
2314317115
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.