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Updated: Feb 24, 2026
Mapping Absolute DNA Density in Cell Nuclei using Single-molecule Localization Microscopy
Published on: November 11, 2025
NSD3 stabilizes nuclear compartmentalization and promotes megabase-scale chromatin interactions
Yi-Hung Chen1,2, John R Collette1, Krupa Sampat1
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Abstract:
Identifying biomolecules that shape nuclear organization is essential for understanding gene regulation in health and disease. Oncogenic fusion proteins rewire chromosome folding and generate biomolecular condensates, but the cofactors of oncoprotein-driven chromatin regulation remain poorly defined, and whether such factors have analogous functions in fusion-naïve cells is unknown. We find that NSD3 mediates chromosome folding in fusion-positive and fusion-negative cells. NSD3 stabilizes the BRD4-NUT fusion oncoprotein on chromatin, promotes histone H3K36me2, and supports oncogene expression while maintaining BRD4-NUT nuclear condensates. NSD3 loss attenuates distant chromatin interactions between BRD4-NUT megadomains both within and between chromosomes. In cells lacking BRD4-NUT, the short, catalytically inactive isoform of NSD3, NSD3short, promotes chromatin contacts separated by multiple megabases. The ability of NSD3short to promote long-range chromatin contacts requires its PWWP domain. By combining chromatin structural analyses in fusion-positive and fusion-negative cells, we show that interrogating fusion oncoprotein-driven chromosome misfolding reveals the multicomponent basis of nuclear compartmentalization and uncovers an adaptor protein that promotes chromatin contacts independent of enzymatic activity.
Insights
NSD3 protein mediates chromosome folding and nuclear organization in both healthy and cancerous cells. It stabilizes oncoproteins, promotes gene expression, and maintains condensate structures, impacting gene regulation.
Area of Science:
- Molecular Biology
- Cell Biology
- Genomics
Background:
- Nuclear organization and chromosome folding are crucial for gene regulation in health and disease.
- Oncogenic fusion proteins disrupt chromosome folding, forming biomolecular condensates, but their cofactors and functions in normal cells are unclear.
Purpose of the Study:
- To identify cofactors involved in oncoprotein-driven chromatin regulation.
- To determine if these cofactors have analogous functions in cells without fusion oncoproteins.
Main Methods:
- Chromatin structural analyses in fusion-positive and fusion-negative cells.
- Investigating the role of NSD3 in stabilizing fusion oncoproteins and promoting histone modifications.
- Assessing the impact of NSD3 loss on chromatin interactions and nuclear condensates.
Main Results:
- NSD3 mediates chromosome folding in both fusion-positive and fusion-negative cells.
- NSD3 stabilizes the BRD4-NUT oncoprotein, promotes H3K36me2, and supports oncogene expression.
- NSD3 loss reduces long-range chromatin interactions; NSD3short promotes contacts via its PWWP domain.
Conclusions:
- NSD3 is a key mediator of chromosome folding and nuclear organization, functioning in both normal and oncogenic contexts.
- NSD3 acts as an adaptor protein, promoting chromatin contacts independently of its enzymatic activity.
- Understanding NSD3's role sheds light on nuclear compartmentalization and gene regulation in cancer.
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