LncRNA Dio3os regulates neighboring gene Dio3 and impacts osteogenesis in trans

Area of Science:

• Endocrinology
• Molecular Biology
• Developmental Biology

Background:

• Consumptive hypothyroidism, a rare pediatric disorder, stems from abnormal Dio3 expression, impacting thyroid hormones and skeletal development.
• The long non-coding RNA Dio3os (lncRNA Dio3os) is implicated in activating Dio3 and inhibiting osteoblast differentiation.

Purpose of the Study:

• To investigate the regulatory role of lncRNA Dio3os in thyroid hormone metabolism and bone formation.
• To explore the mechanisms by which Dio3os influences osteoblast differentiation and skeletal development.

Main Methods:

• Chromatin accessibility (ATAC-seq) and histone modification analyses were performed on mouse and human Dio3os variants.
• Gene expression was analyzed using RNA-seq, and CRISPR-mediated gene editing was employed to delete Dio3os exons.
• Protein binding assays (RUNX2) and manipulation of regulatory factors (HDAC1/2, HIF1a, BMP2, TGFb, Runx2, Brg1) were conducted.

Main Results:

• Dio3os expression is linked to chromatin openness and specific histone modifications at its promoter and key exons.
• Dio3os expression is modulated by various signaling pathways and transcription factors, including thyroid hormones.
• Overexpression of Dio3os increased Dio3 activity and suppressed osteogenic markers; conversely, Dio3os deletion restored osteogenic gene expression and thyroid hormone sensitivity in osteoblasts.

Conclusions:

• lncRNA Dio3os acts as a critical regulator of thyroid hormone inactivation and bone formation.
• Dio3os influences skeletal development by modulating osteoblast differentiation and thyroid hormone signaling.
• Targeting Dio3os presents a potential therapeutic strategy for skeletal abnormalities associated with pediatric hypothyroidism.