A bifunctional imprinted lncRNA scaffolds NuRD-HDAC1 to couple cis-activation of Dio3 with trans-repression of the osteoblast chromatin landscape

Abstract

Long non-coding RNAs (lncRNAs) frequently act at imprinted loci, yet how a single lncRNA can simultaneously activate its neighbor and repress distant genes through a shared chromatin platform remains poorly defined. We show that imprinted Dio3os performs this bifunctional role by scaffolding the nucleosome remodeling and histone deacetylase (NuRD-HDAC1) complex. ATAC-seq and ChIP-seq across osteoblast differentiation reveal that the Dio3-Dio3os bidirectional promoter is dynamically remodeled and co-occupied by HDAC1, HIF1, and active histone marks. CRISPR-mediated exon deletion, CRISPRi, and polyadenylation termination demonstrate that Dio3os activates Dio3 in cis while repressing osteogenic genes in trans. RIP-MS and reverse pulldown identify direct Dio3os-NuRD interaction; ChIP shows the same machinery produces opposing H3K27ac outcomes at Dio3os versus osteogenic promoters. In vivo, osteoblast-specific CRISPRi increases trabecular and cortical bone mass, whereas CRISPRa reduces it in both sexes. Dio3os couples chromatin remodeling to thyroid-hormone metabolism through a context-dependent NuRD scaffold. One sentence summaryDio3os scaffolds NuRD-HDAC1 to activate Dio3 in cis and repress thyroid-hormone-responsive osteogenic genes in trans.