The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass (HIT) - RTDC 5801
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PROVIDER: PRJNA189554 | ENA |
REPOSITORIES: ENA
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Project description:Heparin-induced thrombocytopenia (HIT) is a common drug-induced immune disorder occurring in a subset of heparin-treated patients. Immune complexes comprising heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to its pathogenesis. However, the role of epigenetic modification in HIT remains unexplored. Our study identified JMJD1C, a member of the lysine-specific histone demethylase 3 subfamily, as an essential regulator of PF4/heparin-specific antibody production. While JMJD1C was expressed throughout B-cell development and was dispensable for normal B-cell development, its deficiency disrupted immune tolerance and promoted production of self-reactive antibodies in systemic autoimmune diseases, including PF4/heparin-specific platelet-activating antibodies, a hallmark of pathogenic HIT antibodies. JMJD1C-deficient B cells were hyperresponsive, characterized by enhanced B-cell receptor (BCR)-induced proliferation. Transcriptomic analysis (RNA-Seq) revealed upregulation of pathways associated with BCR signaling, NF-kB activation, the cell cycle, and systemic lupus erythematosus (SLE). CUT&Tag profiling demonstrated that JMJD1C deficiency increased H3K36me1 modification at gene start sites in these pathways, indicating that epigenetic dysregulation drives B-cell hyperactivation. Importantly, transcriptional profiling and regulon analysis of B cells from HIT patients showed enrichment of BCR signaling, cell-cycle, NF-κB, and SLE-associated pathways, closely mirroring those in JMJD1C-deficient B cells. Epigenetic analyses further revealed enhanced promoter chromatin accessibility and elevated H3K36me1 deposition at promoter-TSS regions in HIT B cells. Together, these findings establish a strong molecular overlap between JMJD1C deficiency and human HIT B cells and reveal a previously unrecognized epigenetic mechanism underlying HIT pathogenesis. Our study provides the first evidence linking epigenetic regulation to HIT, offering new insights into its pathophysiology.
2026-04-14 | GSE326619 | GEO
Project description:Heparin-induced thrombocytopenia (HIT) is a common drug-induced immune disorder occurring in a subset of heparin-treated patients. Immune complexes comprising heparin, platelet factor 4 (PF4), and PF4/heparin-reactive antibodies are central to its pathogenesis. However, the role of epigenetic modification in HIT remains unexplored. Our study identified JMJD1C, a member of the lysine-specific histone demethylase 3 subfamily, as an essential regulator of PF4/heparin-specific antibody production. While JMJD1C was expressed throughout B-cell development and was dispensable for normal B-cell development, its deficiency disrupted immune tolerance and promoted production of self-reactive antibodies in systemic autoimmune diseases, including PF4/heparin-specific platelet-activating antibodies, a hallmark of pathogenic HIT antibodies. JMJD1C-deficient B cells were hyperresponsive, characterized by enhanced B-cell receptor (BCR)-induced proliferation. Transcriptomic analysis (RNA-Seq) revealed upregulation of pathways associated with BCR signaling, NF-kB activation, the cell cycle, and systemic lupus erythematosus (SLE). CUT&Tag profiling demonstrated that JMJD1C deficiency increased H3K36me1 modification at gene start sites in these pathways, indicating that epigenetic dysregulation drives B-cell hyperactivation. Importantly, transcriptional profiling and regulon analysis of B cells from HIT patients showed enrichment of BCR signaling, cell-cycle, NF-κB, and SLE-associated pathways, closely mirroring those in JMJD1C-deficient B cells. Epigenetic analyses further revealed enhanced promoter chromatin accessibility and elevated H3K36me1 deposition at promoter-TSS regions in HIT B cells. Together, these findings establish a strong molecular overlap between JMJD1C deficiency and human HIT B cells and reveal a previously unrecognized epigenetic mechanism underlying HIT pathogenesis. Our study provides the first evidence linking epigenetic regulation to HIT, offering new insights into its pathophysiology.
2026-04-14 | GSE327681 | GEO
Project description:The Incidence of Thromboembolic Events in Patients with Antibodies to Heparin-PF4 after Cardiac Bypass (HIT) - RTDC 5801
| PRJNA189555 | ENA
Project description:To identify key plasma proteins altered by heparin challenges and determine its regulatory roles in pathogenic immune complexes formation and thrombosis in HIT
2026-06-30 | GSE318282 | GEO
Project description:To identify key plasma proteins altered by heparin challenges and determine its regulatory roles in pathogenic immune complexes formation and thrombosis in HIT
2026-06-30 | GSE318200 | GEO
Project description:Heparin-Induced Thrombocytopenia - Retrospective Analysis of Data on Incidence and Outcomes Study (HIT_RADIO_BioLINCC)
| PRJNA1428874 | ENA
Project description:Heparin-Induced Thrombocytopenia - Retrospective Analysis of Data on Incidence and Outcomes Study (HIT_RADIO_BioLINCC)
| PRJNA1428873 | ENA
Project description:Pf4 is a filamentous bacteriophage integrated as a prophage into the genome of Pseudomonas aeruginosa PAO1. Pf4 virions can be produced without killing P. aeruginosa. Cell lysis can however occur during superinfection when Pf virions successfully infect a host lysogenized by a Pf superinfective variant. We have previously shown that infection of P. aeruginosa PAO1 with a superinfective Pf4 variant led to abolish twitching motility and to alter biofilm’s architecture. More precisely, the cells embedded into the biofilm were showing for most of them a filamentous morphology, that could be related to the activation of the cell envelope stress response involving both the AlgU and SigX extra cytoplasmic function sigma factors. Herein, we show that Pf4 variant-infection resulted also into a drastic dysregulation of 3,360 genes representing about 58% of P. aeruginosa’s genome, of which about 43% of the virulence factors encoding genes showing a down-regulation. Accordingly, Pf4 variant infection (termed Pf4*) causes in vivo reduction of P. aeruginosa virulence, decreased production of N-acyl-homoserine lactones and 2-alkyl-4-quinolones quorum sensing molecules, and related virulence factors, such as pyocyanin, elastase, and pyoverdine. In addition to virulence encoding genes, expression of genes involved in metabolism, including energy generation and iron homeostasis, was affected, suggesting further relationships between virulence and central metabolism. Altogether, these data suggest that Pf4 phage variant infection results in complex networks dysregulations, leading to reducing acute virulence in P. aeruginosa. This work contributes to the comprehension of the bacterial response to filamentous phage infection.
2022-07-05 | GSE201738 | GEO
Project description:Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to human youthful PF4 signaling, highlighting its potential in rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.
2025-05-31 | GSE280042 | GEO
Project description:Pattern Recognition Receptors (PRRs) modulate tumor immune microenvironments (TIME), but their comparative efficacy remains unclear. Platelet factor 4 (PF4/CXCL4) exhibits paradoxical roles in cancer, and its regulation by PRRs remains unexplored. We systematically evaluated PRR agonists to identify optimal TIME modulators and elucidate PF4’s role. TLR8 agonists optimally remodel TIME by activating PF4-dependent T cell recruitment and engaging PF4-independent ancillary mechanisms. Context-dependent PF4 induction resolves its dual roles in cancer. These findings position TLR8 agonists as promising partners for immunotherapy.
2026-02-18 | GSE305506 | GEO