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Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies [II]

ABSTRACT: Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies [II]

PROVIDER: PRJNA1205729 | ENA |

REPOSITORIES: ENA

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Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies

Project description:The elevated lactate in the joint microenvironment of patients with rheumatoid arthritis (RA) is crucial for disease progression, although the underlying mechanism remains to be elucidated. In this study, we observed significantly increased global lactylation levels within fibroblast-like synoviocytes (FLS) of RA patients compared to HC (healthy controls), and lactylated proteins were enriched in histones. Furthermore, we found that anti-lactated histone antibodies were detected in almost RA patients and positively correlated with Disease Activity Score 28 (DAS28). Then we identified NFATc2 as a key target gene regulated by histone H3 lysine 9 lactylation (H3K9la) using CUT&Tag combined with RNA-seq. Functional studies revealed that NFATc2 promotes migration of RA-FLSs. Additionally, using server combined immune-deficiency (SCID) and collagen-induced arthritis (CIA) mouse models, we demonstrated that NFATc2 exacerbates RA disease progression through enhanced FLS cartilage invasion function. Collectively, our findings suggest that upregulated target gene NFATc2 by lactate-dependent histone lactylation, can be used as a potential therapeutic target for intervention, anti-lactated histone autoantibodies is promising as a diagnostic marker for RA.

2024-12-27 | GSE284403 | GEO

Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies [II]

2025-01-06 | GSE285734 | GEO

Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies [CUT&Tag]

2025-01-06 | GSE284763 | GEO

Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies

Project description:Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies

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Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies [CUT&Tag]

Project description:Lactylated histone promotes rheumatoid arthritis progression by increasing NFATc2 expression and the production of anti-lactylated histone autoantibodies [CUT&Tag]

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Determining the DNA-binding targets of NFATc2 in the AML cell line THP-1

Project description:Based on previous work on the KDM histone demethylase family in AML, the transcription factor NFATC2 was identified as a regulatory target of KDM4A in MLL-AF9-rearrangement THP-1 cells. Our existing work examined the elements of the transcriptome regulated by NFATC2 in THP-1 cells and so, to further this work, we aimed to characterise the DNA-binding targets of NFATc2 in these cells. In this study, we used NFATc2 immunoprecipitation for ChIP-seq in untreated THP-1 cells, in order to determine these.

2024-09-01 | GSE241260 | GEO

Citrullinated IGF2BP1 promotes rheumatoid synovial aggression via increasing the mRNA stability of SEMA3D

Project description:Citrullinated IGF2BP1 promotes rheumatoid synovial aggression via increasing the mRNA stability of SEMA3D

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NFATC2 knock-down on melanoma cell line A375

Project description:RNA-seq on NFATC2 knock-down (siRNA) on melanoma cell line A375

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Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ChIP-seq)

Project description:The transcription factor Nfatc2 is a potent β-cell mitogen in mouse and human islets, however, the direct genomic targets that mediate the mitogenic effects have not been identified. We expressed a constitutively active form of Nfatc2, and the closely related Nfatc1, in human islets and identified ~5,600 differentially expressed genes. Nfatc2 binding sites in human islets were identified via ChIP-seq, yielding ~8,600 high-confidence peaks. By integrating gene expression changes induced by Nfatc2 with genomic binding sites for Nfatc2, we identified ~2,200 direct transcriptional targets of Nfatc2 in human islets. Direct targets that were induced by Nfatc2 were enriched for transcripts that regulate the cell cycle, and for motifs associated with the transcription factor FoxP1. We showed that islets from an endocrine-specific FoxP1, FoxP2 and FoxP4 triple-knockout mouse are less responsive to Nfatc2-induced β-cell proliferation, suggesting the FoxP family may work in concert with Nfatc2 to regulate β-cell proliferation. Nfatc2 induced β-cell proliferation in both mouse and human islets, whereas Nfatc1 does so only in human islets. Exploiting this species difference in Nfatc1-responsiveness, we identified ~250 direct transcriptional targets with similar transcriptional profiles. This gene set strongly enriches for cell cycle-associated transcripts, and includes the nuclear hormone receptor, Nr4a1. We show that deletion of Nr4a1 greatly reduces the capacity of Nfatc2 to induce β-cell proliferation, suggesting that much of the effect on Nfatc2 occurs through its induction of Nr4a1. Integration of ncRNA profiling, chromatin accessibility and Nfatc2 binding sites enabled us to identify key Nfatc2-dependent enhancer loci that mediate enhanced β-cell proliferation.

2021-09-15 | GSE158496 | GEO

Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ATAC-seq)

2021-09-15 | GSE158495 | GEO