The HPSE Gene Insulator-A Novel Regulatory Element That Affects Heparanase Expression, Stem Cell Mobilization, and the Risk of Acute Graft versus Host Disease

• Published in: Cells (Basel, Switzerland) Switzerland), 2021-09, Vol.10 (10), p.2523
• Main Authors: Ostrovsky, Olga, Baryakh, Polina, Morgulis, Yan, Mayorov, Margarita, Bloom, Nira, Beider, Katia, Shimoni, Avichai, Vlodavsky, Israel, Nagler, Arnon
• Format: Article
• Language: English
• Subjects: acute GVHD; Alleles; allogeneic HSCT; Autoimmunity; Binding sites; CD3 antigen; CD34 antigen; Disease prevention; DNA methylation; enhancer; Gene expression; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Gene Frequency - genetics; Gene regulation; Genotype; Genotype & phenotype; Glucuronidase - metabolism; Graft versus host disease; Graft vs Host Disease - genetics; Graft-versus-host reaction; Granulocyte colony-stimulating factor; Hematopoietic Stem Cell Mobilization - methods; Heparan sulfate; HPSE gene; Humans; Informed consent; insulator; Leukocytes (mononuclear); Lymphocytes; Neoplasms - genetics; Neutrophils; Proteins; Single-nucleotide polymorphism; SNPs; Stem cell transplantation; Stem cells; Stem Cells - cytology; Transplantation; Umbilical cord
• ISSN: 2073-4409; 2073-4409
• 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.