Chromatin dysregulation associated with NSD1 mutation in head and neck squamous cell carcinoma
Nargess Farhangdoost,
Cynthia Horth,
Bo Hu,
Eric Bareke,
Xiao Chen,
Yinglu Li,
Mariel Coradin,
Benjamin A. Garcia,
Chao Lu,
Jacek Majewski
Affiliations
Nargess Farhangdoost
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University Genome Centre, Montreal, QC H3A 0G1, Canada
Cynthia Horth
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University Genome Centre, Montreal, QC H3A 0G1, Canada
Bo Hu
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University Genome Centre, Montreal, QC H3A 0G1, Canada
Eric Bareke
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University Genome Centre, Montreal, QC H3A 0G1, Canada
Xiao Chen
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Yinglu Li
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Mariel Coradin
Biochemistry and Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA
Benjamin A. Garcia
Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Chao Lu
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
Jacek Majewski
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University Genome Centre, Montreal, QC H3A 0G1, Canada; Corresponding author
Summary: 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.
