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 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 cis-regulatory 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.

中文翻译：

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NSD1突变导致头颈部鳞状细胞癌的表观基因组异常

表观遗传失调已成为肿瘤发生的重要机制。为了开发针对性的治疗方法，重要的是了解表观遗传修饰基因突变的表观遗传和转录组后果。最近，在最常见和致命的癌症之一的头颈部鳞状细胞癌（HNSCC）的一个子集中，发现了组蛋白甲基转移酶基因NSD1的突变。在这里，我们使用完整的（epi）基因组方法和基因组编辑来剖析HNSCC中NSD1缺失的下游影响。我们证明NSD1突变直接造成基因间H3K36me2域的丢失，然后是DNA甲基化的丢失，以及在受影响的基因组区域中获得H3K27me3。我们进一步表明，这些区域富含顺式调节元件，H3K27ac的后续损失与其靶基因的表达降低相关。我们的分析确定了受NSD1缺失影响的基因和途径，并为进一步了解癌症中染色质修饰之间的相互作用铺平了道路。