Chaim Sheba Medical Center, Department of Hematology and Bone Marrow Transplantation, Tel-Hashomer, Ramat Gan 5266202, Israel.
Technion Integrated Cancer Center, Rappaport Faculty of Medicine, Technion, Haifa 3525433, Israel.
Cells. 2021 Sep 23;10(10):2523. doi: 10.3390/cells10102523.
The HPSE gene encodes heparanase (HPSE), a key player in cancer, inflammation, and autoimmunity. We have previously identified a strong HPSE gene enhancer involved in self-regulation of heparanase by negative feedback exerted in a functional rs4693608 single-nucleotide polymorphism (SNP) dependent manner. In the present study, we analyzed the HPSE gene insulator region, located in intron 9 and containing rs4426765, rs28649799, and rs4364254 SNPs. Our results indicate that this region exhibits HPSE regulatory activity. SNP substitutions lead to modulation of a unique DNA-protein complex that affects insulator activity. Analysis of interactions between enhancer and insulator SNPs revealed that rs4693608 has a major effect on HPSE expression and the risk of post-transplantation acute graft versus host disease (GVHD). The C alleles of insulator SNPs rs4364254 and rs4426765 modify the activity of the HPSE enhancer, resulting in altered HPSE expression and increased risk of acute GVHD. Moreover, rs4426765 correlated with HPSE expression in activated mononuclear cells, as well as with CD3 levels and lymphocyte counts following G-CSF mobilization. rs4363084 and rs28649799 were found to be associated with CD34 levels. Our study provides new insight into the mechanism of HPSE gene regulation and its impact on normal and pathological processes in the hematopoietic system.
HPSE 基因编码肝素酶（HPSE），这是癌症、炎症和自身免疫中的关键因子。我们之前已经鉴定出一个强的 HPSE 基因增强子，它通过负反馈机制在功能性 rs4693608 单核苷酸多态性（SNP）依赖性方式中参与肝素酶的自我调节。在本研究中，我们分析了位于内含子 9 中的 HPSE 基因绝缘子区域，其中包含 rs4426765、rs28649799 和 rs4364254 SNPs。我们的结果表明，该区域具有 HPSE 调节活性。SNP 取代导致独特的 DNA-蛋白质复合物的调节，从而影响绝缘子活性。增强子和绝缘子 SNPs 之间相互作用的分析表明，rs4693608 对 HPSE 表达和移植后急性移植物抗宿主病（GVHD）的风险有主要影响。绝缘子 SNPs rs4364254 和 rs4426765 的 C 等位基因修饰了 HPSE 增强子的活性，导致 HPSE 表达改变和急性 GVHD 的风险增加。此外，rs4426765 与激活的单核细胞中的 HPSE 表达以及 G-CSF 动员后 CD3 水平和淋巴细胞计数相关。rs4363084 和 rs28649799 与 CD34 水平相关。我们的研究为 HPSE 基因调节的机制及其对造血系统中正常和病理过程的影响提供了新的见解。
