SWING domains prime chromatin for nuclear body mediated gene regulation

Nuclear speckles have long been recognized as RNA-rich nuclear bodies, yet their role in genome organization and gene regulation remains incompletely understood. Using a rapid dTAG-mediated degradation system to simultaneously deplete SON and SRRM2--the core structural components of nuclear speckles--we identify a novel class of genomic regions, which we term SWING domains. Upon speckle disruption, SWING domains relocate to the nuclear periphery and acquire repressive histone marks such as H3K9me3, accompanied by transcriptional downregulation, particularly of genes involved in developmental pathways. Notably, human mutations in SON and SRRM2 are associated with neurodevelopmental disorders characterized by intellectual disability and global developmental delay. Patient-derived cells bearing such mutations similarly exhibit SWING-domain relocalization and gene repression, underlining a role for speckles in developmental gene regulation. We also report that previously discovered drug-induced speckle rejuvenation can partially rescue aberrant SWING-domain localization to the nuclear lamina and the associated transcriptome in patient-derived cells and iPSC with acute SON depletion. These findings establish nuclear speckles as key organizers of active chromatin, functioning in opposition to repressive compartments like the nuclear lamina. Our work reveals a mechanism for how nuclear bodies contribute to 3D genome organization and highlights the importance of nuclear speckles in developmental regulation, providing potential avenues for therapeutic intervention. Impact StatementO_LIIdentification of nuclear speckles as determinants of specific 3D genome features. C_LIO_LIDemonstration of functional interactions between opposing nuclear compartments through SWING domains. C_LIO_LIEstablishes developmental relevance of speckle-mediated genome organization. C_LIO_LIProvides potential avenues for therapeutic intervention in speckleopathies. C_LI