The lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, the placement of methylation at lysine 27 of histone H3 (H3K27me2/3), promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.

中文翻译：

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H3K27M-DIPG中的H3K36me2读写器依赖性

组蛋白H3（H3K27M）残基27处的赖氨酸-蛋氨酸突变是弥漫性固有性桥脑胶质瘤（DIPG）的驱动突变，DIPG是一种高度侵袭性的儿科脑肿瘤，没有有效的治疗方法，几乎​​没有生存的机会。H3K27M通过整体抑制PRC2催化活性，甲基化在组蛋白H3（H3K27me2 / 3）的赖氨酸27处的位置来重塑表观基因组，从而促进DIPG的发生。结果，异常升高了对H3K27me2 / 3拮抗的组蛋白修饰H3K36me2。在这里，我们研究了H3K36me2在H3K27M-DIPG中的作用，方法是解决其上游催化酶（写手）和下游结合因子（读手）。我们确定NSD1和NSD2是H3K36me2的主要编写者。H3K27M-DIPG中NSD1 / 2的缺失阻碍了体外细胞增殖和体内肿瘤发生，并破坏促进肿瘤的基因表达程序。此外，我们证明LEDGF和HDGF2是介导NSD1 / 2-H3K36me2下游促肿瘤作用的主要读者。用模拟内源性H3K36me2的化学修饰肽进行处理，可将LEDGF / HDGF2从染色质中移出，并特异性抑制H3K27M-DIPG的增殖。在一起，我们的结果表明，NSD1 / 2-H3K36me2-LEDGF / HDGF2的功能途径是H3K27M-DIPG的后天依赖，并提出了针对治疗干预目标的可能性。用模拟内源性H3K36me2的化学修饰肽进行处理，可将LEDGF / HDGF2从染色质中移出，并特异性抑制H3K27M-DIPG的增殖。在一起，我们的结果表明，NSD1 / 2-H3K36me2-LEDGF / HDGF2的功能途径是H3K27M-DIPG的后天依赖，并提出了针对治疗干预目标的可能性。用模拟内源性H3K36me2的化学修饰肽进行处理，可将LEDGF / HDGF2从染色质中移出，并特异性抑制H3K27M-DIPG的增殖。在一起，我们的结果表明，NSD1 / 2-H3K36me2-LEDGF / HDGF2的功能途径是H3K27M-DIPG的后天依赖，并提出了针对治疗干预目标的可能性。