Chromatin-enriched lncRNAs can act as cell-type specific activators of proximal gene transcription

We recently described a new class of long noncoding RNA defined by especially tight chromatin association, whose presence is strongly correlated with expression of nearby genes in HEK293 cells. Here we critically examine the generality and cis-enhancer mechanism of this class of chromatin enriched RNA (cheRNA). CheRNA are largely cell-type specific, and remain the most effective chromatin signature for predicting cis-gene transcription in all cell types examined. Targeted depletion of three cheRNAs decreases gene expression of their neighbors, indicating potential co-activator function. Single-molecule FISH of one cheRNA-distal target gene pair suggests spatial overlap consistent with a role in chromosome looping. In another example, the cheRNA HIDALGO stimulates the fetal hemoglobin HBG1 gene during erythroid differentiation by promoting contacts to a downstream enhancer. Our results suggest that many cheRNAs activate proximal, lineage-specific gene transcription.