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

• Published in: Cell reports (Cambridge) 2021-02, Vol.34 (8), p.108769-108769, Article 108769
• Main Authors: Farhangdoost, Nargess, Horth, Cynthia, Hu, Bo, Bareke, Eric, Chen, Xiao, Li, Yinglu, Coradin, Mariel, Garcia, Benjamin A., Lu, Chao, Majewski, Jacek
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly; cis-regulatory elements; Computational Biology; Databases, Genetic; DNA Methylation; Epigenesis, Genetic; epigenomics; Gene Editing; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; head and neck squamous cell carcinoma; histone H3 lysine 36 dimethylation; histone modifications; Histone-Lysine N-Methyltransferase - genetics; Humans; Mutation; nuclear receptor binding SET domain protein 1; Squamous Cell Carcinoma of Head and Neck - enzymology; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - pathology; Transcriptome
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108769

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. [Display omitted] •NSD1 directs the interplay between H3K36, H3K27, and DNA methylation in HNSCC•Loss of NSD1 negatively affects the strength of distal intergenic regulatory elements•Downregulated targets of weakened enhancers bridge NSD1 LOF to cancer phenotypes•Primary tumor data from TCGA reflect molecular alterations observed in cell culture Farhangdoost et al. use genome editing and TCGA primary tumor data to provide a link between NSD1 loss, chromatin and regulatory landscape, gene expression, and molecular characteristics of this tumor subtype. Their study extends the understanding of tumorigenic mechanisms underlying head and neck cancers with mutations in NSD1.