RT Journal Article SR Electronic T1 The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis JF bioRxiv FD Cold Spring Harbor Laboratory SP 648279 DO 10.1101/648279 A1 Jordan P. Lewandowski A1 James C. Lee A1 Taeyoung Hwang A1 Hongjae Sunwoo A1 Jill M. Goldstein A1 Abigail F. Groff A1 Nydia Chang A1 William Mallard A1 Adam Williams A1 Jorge Henao-Meija A1 Richard A. Flavell A1 Jeannie T. Lee A1 Chiara Gerhardinger A1 Amy J. Wagers A1 John L. Rinn YR 2019 UL http://biorxiv.org/content/early/2019/05/24/648279.abstract AB RNA has been classically known to play central roles in biology, including maintaining telomeres1, protein synthesis2, and in sex chromosome compensation in certain species3,4. At the center of these important biological systems are noncoding RNAs. While thousands of long noncoding RNAs (lncRNAs) have been identified in mammalian genomes5–8, attributing RNA-based roles to lncRNA loci requires an assessment of whether the observed effect could be due to DNA regulatory elements, the act of transcription, or the lncRNA transcript. Here, we use the syntenically conserved lncRNA locus, Functional intergenic repeating RNA element (Firre), that is located on the X chromosome as a model to discriminate between DNA- and RNA-mediated effects in vivo. To this end, we generated genetically defined loss-of-function, gain-of-function, and rescue mouse models for Firre and provide genetic evidence that the Firre locus produces a trans-acting RNA. We report that: (i) Firre mutant mice have cell-specific defects during hematopoiesis and changes in gene expression that can be rescued by induction of Firre RNA from a transgene in the Firre knockout background, (ii) mice overexpressing Firre from a transgene exhibit increased levels of pro-inflammatory cytokines and impaired survival upon exposure to lipopolysaccharide, and (iii) deletion of the Firre locus did not result in changes in local gene expression on the X chromosome in 9 different biological contexts, suggesting that Firre does not function by cis-acting RNA or DNA elements. Together, our results provide genetic evidence that the Firre locus produces a trans-acting lncRNA that has physiological roles in hematopoiesis and immune function.