Chromatin dysregulation associated with NSD1 mutation in head and neck squamous cell carcinoma.

Abstract

Chromatin dysregulation has emerged as an important mechanism of oncogenesis. To develop targeted treatments, it is important to understand the transcriptomic consequences of mutations in chromatin modifier genes. Recently, mutations in the histone methyltransferase gene nuclear receptor binding SET domain protein 1 (NSD1) have been identified in a subset of common and deadly head and neck squamous cell carcinomas (HNSCCs). Here, we use genome-wide approaches and genome editing to dissect the downstream effects of loss of NSD1 in HNSCC. We demonstrate that NSD1 mutations are responsible for loss of intergenic H3K36me2 domains, followed by loss of DNA methylation and gain of H3K27me3 in the affected genomic regions. In addition, those regions are enriched in cis-regulatory elements, and subsequent loss of H3K27ac correlates with reduced expression of their target genes. Our analysis identifies genes and pathways affected by the loss of NSD1 and paves the way to further understanding the interplay among chromatin modifications in cancer.

• Authors: Nargess Farhangdoost, Cynthia Horth, Bo Hu, Eric Bareke, Xiao Chen, Yinglu Li, Mariel Coradin, Benjamin A Garcia, Chao Lu, Jacek Majewski
• Journal: Cell reports (Cell Rep) Vol. 34 Issue 8 Pg. 108769 (02 23 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 33626351 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• Histone-Lysine N-Methyltransferase
• NSD1 protein, human

Topics

• Cell Line, Tumor
• Chromatin (genetics, metabolism)
• Chromatin Assembly and Disassembly
• Computational Biology
• DNA Methylation
• Databases, Genetic
• Epigenesis, Genetic
• Gene Editing
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Head and Neck Neoplasms (enzymology, genetics, pathology)
• Histone-Lysine N-Methyltransferase (genetics)
• Humans
• Mutation
• Squamous Cell Carcinoma of Head and Neck (enzymology, genetics, pathology)
• Transcriptome