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.

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Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.

Epigenetic dysregulation has emerged as an important mechanism of oncogenesis. To develop targeted treatments, it is important to understand the epigenetic and transcriptomic consequences of mutations in epigenetic modifier genes. Recently, mutations in the histone methyltransferase gene NSD1 have been identified in a subset of head and neck squamous cell carcinomas (HNSCCs)one of the most common and deadly cancers. Here, we use whole (epi)genome approaches and genome editing to dissect the downstream effects of loss of NSD1 in HNSCC. We demonstrate that NSD1 mutations are directly responsible for the loss of intergenic H3K36me2 domains, followed by loss of DNA methylation, and gain of H3K27me3 in the affected genomic regions. We further show that those regions are enriched in cisregulatory elements and that 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.regions defined in Fig. 3a as "cluster B"); median values are shown at the top. e Spearman correlation of differential enrichment between NSD1-WT vs KO and WT vs MT.

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