Laboratory of Theoretical Biophysics, School oef Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China.
Laboratory of Theoretical Biophysics, School oef Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China.
Gene. 2021 Nov 15;802:145862. doi: 10.1016/j.gene.2021.145862. Epub 2021 Aug 3.
Chronic myelogenous leukemia (CML) is a malignant clonal disease of hematopoietic stem cells. Researches have exhibited that the progression of CML is related to histone modifications. Here, we perform the systematic analyses of H3K36me3 patterns and gene expression level changes. We observe that the genes with higher gene-body H3K36me3 levels in normal cells show fewer expression changes during leukemogenesis, while the genes with lower gene-body H3K36me3 levels in normal cells yield obvious expression changes during leukemogenesis (ρ = -0.98, P = 9.30 × 10). These findings are conserved in human lung/breast cancers and mouse CML, regardless of gene expression levels and gene lengths. Regulatory element analysis and Random Forest regression display that Hoxd13, Rara, Scl, Smad3, Smad4 and Tgif1 induce the up-regulation of genes with lower H3K36me3 levels (ρ = 0.97, P = 2.35 × 10). Enrichment analysis shows that the differentially expressed genes with lower H3K36me3 levels are involved in leukemia-related pathways, such as leukocyte migration and regulation of leukocyte activation. Finally, six driver genes (Tp53, Wt1, Dnmt3a, Cacna1b, Phactr1 and Gbp4) with lower H3K36me3 levels are identified. Our analyses indicate that lower gene-body H3K36me3 levels may serve as a biomarker for the progression of CML.
慢性髓系白血病（CML）是一种造血干细胞的恶性克隆性疾病。研究表明，CML 的进展与组蛋白修饰有关。在这里，我们对 H3K36me3 模式和基因表达水平变化进行了系统分析。我们观察到，在正常细胞中，基因体 H3K36me3 水平较高的基因在白血病发生过程中表达变化较少，而在正常细胞中基因体 H3K36me3 水平较低的基因在白血病发生过程中表达变化明显（ρ=-0.98，P=9.30×10）。这些发现无论是在人类肺癌/乳腺癌还是在小鼠 CML 中都具有保守性，与基因表达水平和基因长度无关。调控元件分析和随机森林回归显示，Hoxd13、Rara、Scl、Smad3、Smad4 和 Tgif1 诱导基因体 H3K36me3 水平较低的基因上调（ρ=0.97，P=2.35×10）。富集分析表明，基因体 H3K36me3 水平较低的差异表达基因参与了与白血病相关的途径，如白细胞迁移和白细胞激活的调节。最后，鉴定出六个基因（Tp53、Wt1、Dnmt3a、Cacna1b、Phactr1 和 Gbp4）的基因体 H3K36me3 水平较低，其驱动作用。我们的分析表明，基因体 H3K36me3 水平较低可能作为 CML 进展的生物标志物。
