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Short Tandem Repeats of Single-Stranded (ATTCC)n in Neutrophil Extracellular Traps Bind Thrombin

ABSTRACT: DNA-protein interactions play a pivotal role in a variety of cellular processes. Despite the considerable research dedicated to understanding these interactions, the specific role of single-stranded DNA (ssDNA) remains largely unexplored. Our study aimed to uncover the role of ssDNA in the interplay between neutrophil extracellular traps (NETs) and thrombin, a crucial enzyme involved in both blood clot formation and immune response. Using chromatin immunoprecipitation sequencing (ChIP-seq) and kethoxal-assisted ssDNA sequencing, we identified a specific short tandem repeat (STR) sequence, ss(ATTCC)n, that is highly enriched and forms an iI-motif structure crucial for its interaction with thrombin. We further observed that the binding affinity between ss(ATTCC)n and thrombin is increased under acidic conditions, a condition frequently linked to diseases such as cancer. Our findings not only shed light on the unexplored area of sequence-dependent ssDNA-protein interactions but also pave the way for targeted interventions in thrombosis and coagulation disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253483 | GEO | 2025/05/29

REPOSITORIES: GEO

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Project description:Cysteinyl leukotrienes (cysLT), i.e. LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway. The cysLT receptors cysLT1-R and cysLT2-R are expressed on different target cells and mediate inflammatory reactions in tissue- and LT-R-specific ways. Though endothelial cells (ECs) predominantly express cysLT2-Rs, their role in vascular biology remains to be defined. To delineate cysLT2-R´s action, we stimulated human umbilical vein EC with 100 nM LTD4 for 60 min, determined gene signatures by microarrays, and characterized the resulting EC phenotypes. As controls, we compared LTD4-induced genes with those induced by 10 nM thrombin, a prototype vasoactive activator of EC that binds to protease-activated receptor 1 (PAR-1). Following application of stringent filters 37 LTD4-upregulated genes were identified (> 2.5fold stimulation). Surprisingly, most of the LTD4-regulated genes were also induced by thrombin and expression of cysLT2-R- and PAR-1-regulated genes strongly correlated (Pearson correlation coefficient: r = 0.90). Moreover, LTD4 + thrombin, when added together, augmented expression of LTD4- or thrombin-stimulated genes (Wilcoxon signed rank test: p < 0.01). Prominently induced genes that may play roles in vascular injury were studied in detail: Early growth response (EGR) and nuclear receptor subfamily 4 group A; E-selectin; CXC ligand 2; interleukin 8 (IL-8); a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1 (ADAMTS-1); and tissue factor (TF). Transcripts of these genes peaked at approximately 60 min, were unaffected by the cysLT1-R antagonist montelukast, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus in LTD4-stimulated cells; LTD4 upregulated IL-8 formation and secretion; and LTD4 raised TF protein and TF-dependent EC pro-coagulant activity. These data show that cysLT2-R activation results in a pro-inflammatory EC phenotype through activation of immediate-early genes that resemble those induced by PAR-1. As LTD4 and thrombin are formed concomitantly during vascular injury and pro-thrombotic states, cysLT2-R and PAR-1 may collaborate in vivo to mediate vascular injury and repair. Keywords: Leukotriene Transcriptome, Thrombin Transcriptome, HUVEC, Immediate-Early Gene Expression, Cysteinyl Leukotriene 2 Receptor Gene Signature in HUVEC

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Short Tandem Repeats of Single-Stranded (ATTCC)n in Neutrophil Extracellular Traps Bind Thrombin

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