表观遗传修饰,包括DNA甲基化和组蛋白翻译后修饰,通过影响高等生物的DNA可及性和染色质结构来复杂地调节基因表达模式。这些修改是可遗传的,独立于初级DNA序列,在发展和分化过程中发生动态变化,并且经常在人类疾病中受到干扰。表观遗传修饰的可逆性使它们成为治疗干预和靶向表观遗传调节剂的药物的有希望的靶标(例如,tazemetostat,靶向H3K27甲基转移酶EZH2)已应用于多种癌症的临床治疗。H3K36甲基转移酶的NSD家族-包括NSD1(KMT3B),NSD2(MMSET/WHSC1),和NSD3(WHSC1L1)-现在正在受到药物开发的关注,随着NSD2抑制剂(KTX-1001)的令人兴奋的出现,已进入复发性或难治性多发性骨髓瘤的I期临床试验。NSD蛋白识别和催化组蛋白赖氨酸标记的甲基化,从而调节染色质完整性和基因表达。多项研究表明NSD蛋白与人类疾病有关,注意到易位的影响,异常表达,和各种功能失调的体细胞突变。这里,我们回顾了NSD蛋白的生物学功能,与NSD蛋白相关的表观遗传合作,越来越多的证据将这些蛋白质与发育障碍和肿瘤发生联系起来,同时还考虑了创新表观遗传疗法的发展前景。
Epigenetic modifications, including DNA methylation and histone post-translational modifications, intricately regulate gene expression patterns by influencing DNA accessibility and chromatin structure in higher organisms. These modifications are heritable, are independent of primary DNA sequences, undergo dynamic changes during development and differentiation, and are frequently disrupted in human diseases. The reversibility of epigenetic modifications makes them promising targets for therapeutic intervention and drugs targeting epigenetic regulators (e.g., tazemetostat, targeting the H3K27 methyltransferase EZH2) have been applied in clinical therapy for multiple cancers. The NSD family of H3K36 methyltransferase enzymes-including NSD1 (KMT3B), NSD2 (MMSET/WHSC1), and NSD3 (WHSC1L1)-are now receiving drug development attention, with the exciting advent of an NSD2 inhibitor (KTX-1001) advancing to Phase I clinical trials for relapsed or refractory multiple myeloma. NSD proteins recognize and catalyze methylation of histone lysine marks, thereby regulating chromatin integrity and gene expression. Multiple studies have implicated NSD proteins in human disease, noting impacts from translocations, aberrant expression, and various dysfunctional somatic mutations. Here, we review the biological functions of NSD proteins, epigenetic cooperation related to NSD proteins, and the accumulating evidence linking these proteins to developmental disorders and tumorigenesis, while additionally considering prospects for the development of innovative epigenetic therapies.