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bioRxiv · 10.1101/2025.04.14.647401

LncRNA Dio3os regulates neighboring gene Dio3 and impacts osteogenesis in trans

Hassan, Q.·Chen, Y.·Wldman, B. J.·Rehn, M.·Mishra, S.
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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.

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Hassan, Q., Chen, Y., Wldman, B. J., Rehn, M., Mishra, S.. 2025-04-14. LncRNA Dio3os regulates neighboring gene Dio3 and impacts osteogenesis in trans. https://doi.org/10.1101/2025.04.14.647401

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