近期大规模基因组测序发现许多组蛋白H3突变在青少年癌症中有极高的发生率。功能研究表明这些突变都具有原癌作用，随之这些组蛋白H3突变被称为原癌组蛋白。其中原癌组蛋白H3.3K36M在软骨母细胞瘤中的发生率超过90%。长期以来，人们对表观遗传信息改变在癌症细胞抗药性中的作用进行了深入的研究，然而对其如何像原癌基因一样导致癌症形成还知之甚少。本课题拟在之前对原癌组蛋白H3.3K36M的研究基础上，进一步通过体外组蛋白甲基化实验探索不同组蛋白H3中K36M突变对相应甲基转移酶的作用。同时通过高通量测序，研究K36M突变发生于不同组蛋白H3时，细胞内组蛋白修饰和DNA甲基化的表观遗传重编程过程。最后通过对细胞表型、基因表达和非转录起始的研究，进一步揭示原癌组蛋白H3.3K36M诱导软骨母细胞瘤形成的分子机制，从而为软骨母细胞瘤的精准治疗提供潜在的治疗靶点。

Recently, it's found that several types of pediatric cancers contain high frequent mutations in histone H3, and these mutant histones show oncogenic effects. Thereafter, these mutant histones are so-called oncohistones, of which over 90% of chondroblastomas contain an H3.3K36M mutation. The functions of epigenetic changes in drug resistance of tumors have been studied thoroughly. However, it's still unknown how epigenetic changes promote tumorigenesis. In the light of our previous studies about the function of H3.3K36M in the tumorigenesis of chondroblastoma, we will further study the impacts of different H3K36M mutations on the H3K36 methyltransferases in vitro. In addition, we will profile the reprogramming of epigenetic information, including histone modification and DNA methylation, in different H3K36M mutant cells through high-throughput sequencing. We will also study the cellular phenotype, genes expression and spurious transcription initiation in the mutant cells. These studies will elucidate the molecular mechanism how oncohistone H3.3K36M induces tumorigenesis, and provide novel and urgently therapeutic targets for the precision medicine.