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Updated: Jul 31, 2025
10:41
An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues
Published on: April 5, 2018
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Cell state-dependent chromatin targeting in NUT carcinoma
Artyom A Alekseyenko1,2,3, Barry M Zee1,2,4, Zuzer Dhoondia1,2
1Div. of Genetics, Dept. of Medicine, Brigham and Women's Hospital, Boston, MA.
Biorxiv : the Preprint Server for Biology
|May 3, 2023
Summary
The oncogenic BRD4-NUT fusion protein creates large DNA regions called megadomains. Their location depends critically on the cell's initial state, not just its genome sequence.
Area of Science:
- Cancer Biology
- Chromatin Regulation
- Epigenetics
Background:
- Aberrant transcriptional programming and chromatin dysregulation are hallmarks of cancer, often leading to undifferentiated cell growth.
- The BRD4-NUT fusion protein, a combination of two chromatin regulators, drives aggressive NUT carcinoma.
- Previous studies showed varied megadomain locations in different patient cell lines, raising questions about the cause.
Approach:
- Investigated the role of cell state in BRD4-NUT megadomain formation using a human stem cell model.
- Compared megadomain patterns in pluripotent stem cells versus cells induced into a mesodermal lineage.
- Analyzed c-MYC protein-protein interactions in a patient cell line.
Key Points:
- BRD4-NUT fusion induces large, hyperacetylated genomic regions (megadomains).
- Megadomain locations differ significantly between pluripotent and mesodermally-induced cells.
- Initial cell state, not just genome sequence, dictates megadomain positioning.
Conclusions:
- Cellular epigenetic state is a critical determinant of BRD4-NUT megadomain formation.
- These findings suggest a cascade of chromatin misregulation underlies NUT carcinoma development.
- Understanding megadomain localization provides insights into cancer progression and potential therapeutic targets.
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