RNA binds select autosomal genes and depends on Repeat B to regulate their expression.

a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, 's ability to diffuse under select circumstances has also been documented, leading us to suspect that RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate that RNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status. binds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for human RNA. We find that binding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi, binding does not lead to full silencing and also does not spread beyond the target gene. Over-expressing in transgenic ES cells similarly leads to autosomal gene suppression, while deleting 's Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with the inhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal that targets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by a small molecule inhibitor.