Nuclear pore complexes (NPCs) and their constituent nucleoporins (Nups) play essential roles in chromatin organization and gene regulation, yet their functions in osteoclastogenesis remain unclear. Here, we showed that most Nups were down-regulated during osteoclast differentiation. Overexpression of Y-complex Nup133 impaired osteoclast formation by enhancing NPC assembly. We identified that chromatin underwent dynamic reorganization during osteoclast maturation and multinucleation, marked by heterochromatin shifts from the nuclear periphery to the nuclear center, regulated by NPCs. ATAC-seq data revealed increased accessibility of Dnmt3a and Ezh2 , while most genes became less accessible. Inhibition of Dnmt3a and Ezh2 disrupted osteoclast differentiation and protected against bone loss in osteoporotic mice. Comprehensive analyses using H3K27me3 and H3K27ac ChIP-seq, together with DNA methylation-seq, showed descriptive changes in epigenetic features during osteoclastogenesis. These findings highlight the significant roles of NPCs and epigenetic regulators in osteoclastogenesis, offering new insights into potential therapeutic targets for bone diseases.
Qu et al. (Sun,) studied this question.