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

We used the Functional intergenic repeating RNA element (Firre) locus - a conserved intergenic lncRNA gene that is located on the X chromosome11,12 - as a model to discriminate DNA- and RNA-mediated effects in vivo. Using genetically defined loss-of-function, gain-of-function, and rescue mouse models for Firre, we identify cell-specific defects during hematopoiesis and immune function. This includes impaired survival upon lipopolysaccharide challenge and diminished production of immune cells in Firre knockout mice. We show that these defects can be rescued by induction of Firre RNA from a transgene in the Firre knockout background. Moreover, upon ectopic induction of Firre expression, we observe an in vivo rescue of gene expression programs that were lost in the Firre knockout model. Finally, we show that unlike most regulatory DNA and RNA species, which function locally to regulate the expression of neighboring genes, Firre RNA acts in trans to alter cellular functions. Comparision of WT, KO and rescue by RNA-seq