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

Jordan P Lewandowski,Jorge Henao-Meija,John L Rinn,Amy J Wagers,Jeannie T Lee,Taeyoung Hwang,Chiara Gerhardinger,Nydia P Chang,Adam Williams,Hongjae Sunwoo,William Mallard,Jill M Goldstein,James C Lee,Richard A Flavell,Abigail F Groff

doi:10.1038/s41467-019-12970-4

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.

Highlights

RNA has been classically known to play central roles in biology, including maintaining telomeres, protein synthesis, and in sex chromosome compensation
Since noncoding RNAs have been described to be generally expressed at lower levels compared with protein-coding genes[32,33,34,35], we determined the relative abundance of Firre RNA in vivo
Classic models used to study noncoding RNAs—ribosomal RNAs, small nucleolar RNAs, tRNAs, and the telomerase RNA component (TERC)—have demonstrated that RNAs serve important cellular functions

Summary

Introduction

RNA has been classically known to play central roles in biology, including maintaining telomeres, protein synthesis, and in sex chromosome compensation. We use the functional intergenic repeating RNA element, (Firre) locus as a model to discriminate between DNAand RNA-mediated effects in vivo. We selected this locus for our study because it is syntenically conserved in a number of mammals, including human[14,15,16,17], and because studies have reported diverse biological and molecular roles. The Firre locus does not contain cis-acting RNA or DNA elements (including the promoter) that regulate neighboring gene expression on the X chromosome (nine biological contexts examined), suggesting that Firre does not function in cis. Our study provides evidence for a trans-acting RNA-based role for the Firre locus that, far, has physiological importance for hematopoiesis

Methods

Results

Conclusion