NSD3 stabilizes nuclear compartmentalization and promotes megabase-scale chromatin interactions.

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.