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  1. Article ; Online: A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

    Wouter J. Venema / Sanne Hiddingh / Jorg van Loosdregt / John Bowes / Brunilda Balliu / Joke H. de Boer / Jeannette Ossewaarde-van Norel / Susan D. Thompson / Carl D. Langefeld / Aafke de Ligt / Lars T. van der Veken / Peter H.L. Krijger / Wouter de Laat / Jonas J.W. Kuiper

    Cell Genomics, Vol 4, Iss 1, Pp 100460- (2024)

    2024  

    Abstract: Summary: Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ...

    Abstract Summary: Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
    Keywords ERAP2 ; GWAS ; autoimmunity ; SNP ; eQTL ; rs2248374 ; Genetics ; QH426-470 ; Internal medicine ; RC31-1245
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Stiffness-Induced Endothelial DLC-1 Expression Forces Leukocyte Spreading through Stabilization of the ICAM-1 Adhesome

    Lilian Schimmel / Miesje van der Stoel / Carmela Rianna / Anne-Marieke van Stalborch / Aafke de Ligt / Mark Hoogenboezem / Simon Tol / Jos van Rijssel / Robert Szulcek / Harm Jan Bogaard / Patrick Hofmann / Reinier Boon / Manfred Radmacher / Vivian de Waard / Stephan Huveneers / Jaap D. van Buul

    Cell Reports, Vol 24, Iss 12, Pp 3115-

    2018  Volume 3124

    Abstract: Summary: Leukocytes follow the well-defined steps of rolling, spreading, and crawling prior to diapedesis through endothelial cells (ECs). We found increased expression of DLC-1 in stiffness-associated diseases like atherosclerosis and pulmonary arterial ...

    Abstract Summary: Leukocytes follow the well-defined steps of rolling, spreading, and crawling prior to diapedesis through endothelial cells (ECs). We found increased expression of DLC-1 in stiffness-associated diseases like atherosclerosis and pulmonary arterial hypertension. Depletion of DLC-1 in ECs cultured on stiff substrates drastically reduced cell stiffness and mimicked leukocyte transmigration kinetics observed for ECs cultured on soft substrates. Mechanistic studies revealed that DLC-1-depleted ECs or ECs cultured on soft substrates failed to recruit the actin-adaptor proteins filamin B, α-actinin-4, and cortactin to clustered ICAM-1, thereby preventing the ICAM-1 adhesome formation and impairing leukocyte spreading. This was rescued by overexpressing DLC-1, resulting in ICAM-1 adhesome stabilization and leukocyte spreading. Our results reveal an essential role for substrate stiffness-regulated endothelial DLC-1, independent of its GAP domain, in locally stabilizing the ICAM-1 adhesome to promote leukocyte spreading, essential for efficient leukocyte transendothelial migration. : Leukocyte extravasation depends on local cellular and substrate stiffness. Schimmel et al. identified endothelial DLC-1 as a mediator to translate stiffness to leukocyte behavior. DLC-1 is crucial for the ICAM-1 adhesome, which allows leukocytes to switch from the rolling to the spreading and crawling phase, followed by diapedesis. Keywords: ICAM-1, DLC-1, spreading, leukocyte, transmigration, diapedesis, rolling, stiffness, mechanosignaling, endothelial
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2018-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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