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      Identification of strong intron enhancer in the heparanase gene: effect of functional rs4693608 variant on HPSE enhancer activity in hematological and solid malignancies

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          Abstract

          Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of heparan sulfate (HS) proteoglycans and releases HS-bound cytokines, chemokines, and bioactive growth-promoting factors. Heparanase plays an important role in the nucleus as part of an active chromatin complex. Our previous studies revealed that rs4693608 correlates with heparanase levels and increased risk of acute and extensive chronic graft vs. host disease (GVHD). Discrepancy between recipient and donor in this SNP significantly affected the risk of acute GVHD. In the present study, we analyzed the HPSE gene region, including rs4693608, and demonstrated that this region exhibits SNPs-dependent enhancer activity. Analysis of nuclear proteins from normal leukocytes revealed their binding to DNA probe of both alleles with higher affinity to allele G. All malignant cell lines and leukemia samples disclosed a shift of the main bands in comparison to normal leukocytes. At least five additional shifted bands were bound to allele A while allele G probe was bound to only one main DNA/protein complex. Additional SNPs rs4693083, rs4693084, and rs4693609 were found in strong linkage disequilibrium (LD) with rs11099592 (exon 7). Only rs4693084 affected protein binding to DNA in cell lines and leukemia samples. As a result of the short distance between rs4693608 and rs4693084, both SNPs may be included in a common DNA/protein complex. DNA pull-down assay revealed that heparanase is involved in self-regulation by negative feedback in rs4693608-dependent manner. During carcinogenesis, heparanase self-regulation is discontinued and the helicase-like transcription factor begins to regulate this enhancer region. Altogether, our study elucidates conceivable mechanism(s) by which rs4693608 SNP regulates HPSE gene expression and the associated disease outcome.

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          The selection and function of cell type-specific enhancers.

          The human body contains several hundred cell types, all of which share the same genome. In metazoans, much of the regulatory code that drives cell type-specific gene expression is located in distal elements called enhancers. Although mammalian genomes contain millions of potential enhancers, only a small subset of them is active in a given cell type. Cell type-specific enhancer selection involves the binding of lineage-determining transcription factors that prime enhancers. Signal-dependent transcription factors bind to primed enhancers, which enables these broadly expressed factors to regulate gene expression in a cell type-specific manner. The expression of genes that specify cell type identity and function is associated with densely spaced clusters of active enhancers known as super-enhancers. The functions of enhancers and super-enhancers are influenced by, and affect, higher-order genomic organization.
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            Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis.

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              Heparanase: roles in cell survival, extracellular matrix remodelling and the development of kidney disease

              Heparanase is an endoglycosidase that regulates numerous cell functions and is able to degrade the extracellular matrix component heparan sulfate, which has a key role in maintaining the integrity of the glomerular filtration barrier. In this Review, Rabelink and colleagues describe the biological regulation and functions of heparanase, including the role of this enzyme in the development of kidney disease.
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                Author and article information

                Contributors
                972-3-5305770 , olga.ostrovsky@sheba.health.gov.il
                Journal
                Oncogenesis
                Oncogenesis
                Oncogenesis
                Nature Publishing Group UK (London )
                2157-9024
                29 June 2018
                29 June 2018
                June 2018
                : 7
                : 6
                : 51
                Affiliations
                [1 ]ISNI 0000 0001 2107 2845, GRID grid.413795.d, Department of Hematology and Bone Marrow Transplantation, , Chaim Sheba Medical Center, ; Tel-Hashomer, Israel
                [2 ]ISNI 0000000121102151, GRID grid.6451.6, Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, , Technion, ; Haifa, Israel
                Article
                60
                10.1038/s41389-018-0060-8
                6023935
                1cc94a8e-fbf3-4c33-9416-c5e2ee859cb3
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 5 September 2017
                : 3 May 2018
                : 20 May 2018
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                © The Author(s) 2018

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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