SWING regions prime chromatin for nuclear speckle–mediated gene regulation

Yu, Ruofan, Sas-Nowosielska, Hanna, Dessai, Abhisha Sawant, Oubarri, Amal, Kim, Hannah, Faunce, Christine L, Vanderkruk, Ben, Good, Charly R, Alexander, Katherine A, Nguyen, Son C, Krantz, Ian D, Joyce, Eric F, Lakadamyali, Melike, Berger, Shelley L (October 2025) SWING regions prime chromatin for nuclear speckle–mediated gene regulation. bioRxiv. ISSN 2692-8205 (Submitted)

PDF 10.1101.2025.10.01.679801.pdf - Submitted Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (14MB)

Abstract

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. 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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > nuclear speckles
CSHL Authors:	Alexander, Katherine
Communities:	CSHL labs > Alexander lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	3 October 2025
Date Deposited:	08 Jul 2026 15:23
Last Modified:	08 Jul 2026 15:23
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42263

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