Epigenetics-mediated pathological alternations and their potential in antiphospholipid syndrome diagnosis and therapy

Tan, Yuan; Liu, Qi; Li, Zhongxin; Yang, Shuo; Cui, Liyan

doi:10.1016/j.autrev.2022.103130

Cited by 11 publications

(15 citation statements)

References 114 publications

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“…The role of syncytins in APS pathogenesis also remains unknown, although some recent studies have reported an altered lncRNA signature in these patients compared with controls [32,33]. Indeed, lncRNAs may contribute to several steps of APS pathogenesis, including leukocyte activation, immunothrombosis, and impaired embryonic development [34], but whether these events are influenced by the abnormal expression of syncytin genes has not been investigated to date.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Long Noncoding RNAs and Syncytin-1/Syncytin-2 Genes and Transcripts: How Noncoding RNAs May Affect Pregnancy in Patients with Systemic Lupus Erythematosus

Talotta

2023

IJMS

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Background: Patients with systemic lupus erythematosus (SLE) often suffer from obstetric complications not necessarily associated with the antiphospholipid syndrome. These events may potentially result from the reduced placental synthesis of the fusogenic proteins syncytin-1 and syncytin-2, observed in women with pregnancy-related disorders. SLE patients have an aberrant noncoding (nc)RNA signature that may in turn dysregulate the expression of syncytin-1 and syncytin-2 during placentation. The aim of this research is to computationally evaluate and characterize the interaction between syncytin-1 and syncytin-2 genes and human ncRNAs and to discuss the potential implications for SLE pregnancy adverse outcomes. Methods: The FASTA sequences of the syncytin-1 and syncytin-2 genes were used as inputs to the Ensembl.org library to find any alignments with human ncRNA genes and their transcripts, which were characterized for their tissue expression, regulatory activity on adjacent genes, biological pathways, and potential association with human disease. Results: BLASTN analysis revealed a total of 100 hits with human long ncRNAs (lncRNAs) for the syncytin-1 and syncytin-2 genes, with median alignment scores of 151 and 66.7, respectively. Only lncRNAs TP53TG1, TTTY14, and ENSG00000273328 were reported to be expressed in placental tissue. Dysregulated expression of lncRNAs TP53TG1, LINC01239, and LINC01320 found in this analysis has previously been described in SLE patients as well as in women with a high-risk pregnancy. In addition, some of the genes adjacent to lncRNAs aligned with syncytin-1 or syncytin-2 in a regulatory region might increase the risk of pregnancy complications or SLE. Conclusions: This is the first computational study showing alignments between syncytin-1 and syncytin-2 genes and human lncRNAs. Whether this mechanism affects syncytiotrophoblast morphogenesis in SLE females is unknown and requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Interaction between Long Noncoding RNAs and Syncytin-1/Syncytin-2 Genes and Transcripts: How Noncoding RNAs May Affect Pregnancy in Patients with Systemic Lupus Erythematosus

Talotta

2023

IJMS

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“…Previous studies have shown that aPL in serum is closely related to thrombosis in children with SLE and APS. aPL is a group of antibodies that immunoreact with a variety of antigenic substances containing phospholipid structures, including LAC, aCL and anti- β 2GP1 antibodies, causing thrombus formation by influencing coagulation, anticoagulation and fibrinolysis ( 6 ). SLE patients are prone to thrombi due to vasculitis, hypoalbuminemia and other reasons, and the incidence of thrombosis increases significantly after APS is combined ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…SLE is a common cause of secondary nephrotic syndrome (NS), some SLE children started the disease with NS, and up to 2/3 of pediatric SLE patients evaluated in large medical centers had some degree of renal involvement ( 4 , 5 ). APS is an autoimmune disease involving multi-systems characterized by recurrent arterial and/or venous thrombosis, abnormal pregnancy, and persistence of antiphospholipid antibodies ( 6 ). APS is classified into primary APS and secondary APS, usually associated with SLE ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: A case of recurrent thrombosis in pediatric antiphospholipid syndrome associated with pediatric onset systemic lupus

Liu

Liu²,

Zhang³

et al. 2023

Front. Pediatr.

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Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-system involvement as the main manifestation, and has complex and diverse clinical features. Studies on large samples have revealed that SLE patients have a significantly increased risk of thrombotic events, which are also one of the important causes of morbidity and mortality in SLE patients. Antiphospholipid syndrome (APS) is a rare autoimmune disorder characterized by recurrent arterial and venous thrombosis, pregnancy-related complications, and the persistence of antiphospholipid antibodies at a 12-week interval. There are few reports about SLE coexisting with APS in children. This paper reported a school-age patient who started the disease with gross hematuria after bumping into the waist. The initial diagnosis of renal contusion was then confirmed by color Doppler ultrasound as renal vein and inferior vena cava embolism. She suddenly developed severe chest pain and dyspnea 3 days after hospitalization. And imaging supported pulmonary embolism with massive proteinuria, hypoalbuminemia, and hypercholesterolemia. The initial diagnosis was nephrotic syndrome (NS) with arteriovenous embolization, and popliteal vein embolism occurred again 5 years later, and she was thus diagnosed with SLE coexisting with APS. Afterwards, we discussed the possible mechanism and therapeutic strategies of SLE&APS that started with nephrotic syndrome, in order to achieve early identification and treatment of the disease and improve the prognosis of children.

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“…In addition, they are involved in activating endothelial cells, neutrophils, platelets and monocytes and releasing inflammatory mediators and coagulation factors 2,3 . Although in vitro studies and animal experiments have revealed the involvement of epigenetics in the pathogenesis of APS, including long non‐coding RNAs (lncRNAs) and cytosine‐phosphate‐guanine (CpG) methylation at the promoters of genes, 4–6 the mechanisms of histone modification in its occurrence and development remain to be elucidated 3,7 …”

Section: Introductionmentioning

confidence: 99%

“…2,3 Although in vitro studies and animal experiments have revealed the involvement of epigenetics in the pathogenesis of APS, including long noncoding RNAs (lncRNAs) and cytosine-phosphate-guanine (CpG) methylation at the promoters of genes, [4][5][6] the mechanisms of histone modification in its occurrence and development remain to be elucidated. 3,7 Trimethylation of histone 3 lysine 4 (H3K4me3) is a major histone modification, resulting in dynamic alterations of chromatin accessibility and the expression of inflammation-related genes, suggesting its potential role in the pathogenesis of APS. 8,9 The interaction of WD repeat domain 5 (WDR5), a H3K4 presenter that forms the COMPASS complex together with ASH2L, DPY30 and RBBP5, 10 with H3K4 methyltransferase MLL1 mainly catalyses the deposition of the H3K4me3 mark.…”

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confidence: 99%

ARID5B‐mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in β2GPI/anti‐β2GPI‐treated monocytes

Tan,

Qiao,

Yang

et al. 2024

Clinical & Translational Med

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BackgroundAlterations of the trimethylation of histone 3 lysine 4 (H3K4me3) mark in monocytes are implicated in the development of autoimmune diseases. Therefore, the purpose of our study was to elucidate the role of H3K4me3‐mediated epigenetics in the pathogenesis of antiphospholipid syndrome (APS).MethodsH3K4me3 Cleavage Under Targets and Tagmentation and Assay for Transposase‐Accessible Chromatin were performed to determine the epigenetic profiles. Luciferase reporter assay, RNA immunoprecipitation, RNA pull‐down, co‐immunoprecipitation and chromatin immunoprecipitation were performed for mechanistic studies. Transmission electron microscopy and propidium iodide staining confirmed cell pyroptosis. Primary monocytes from patients with primary APS (PAPS) and healthy donors were utilised to test the levels of key molecules. A mouse model mimicked APS was constructed with beta2‐glycoprotein I (β2GPI) injection. Blood velocity was detected using murine Doppler ultrasound.ResultsH3K4me3 signal and open chromatin at the ARID5B promoter were increased in an in vitro model of APS. The epigenetic factor ARID5B directly activated LINC01128 transcription at its promoter. LINC01128 promoted the formation of the BTF3/STAT3 complex to enhance STAT3 phosphorylation. Activated STAT3 interacted with the NLRP3 promoter and subsequently stimulated pyroptosis and apoptosis. ARID5B or BTF3 depletion compensated for LINC01128‐induced pyroptosis and apoptosis by inhibiting STAT3 phosphorylation. In mice with APS, β2GPI exposure elevated the levels of key proteins of pyroptosis and apoptosis pathways in bone marrow‐derived monocytes, reduced the blood velocity of the ascending aorta, increased the thrombus size of the carotid artery, and promoted the release of interleukin (IL)‐18, IL‐1β and tissue factor. Patients with PAPS had the high‐expressed ARID5B and LINC01128, especially those with triple positivity for antiphospholipid antibodies. Moreover, there was a positive correlation between ARID5B and LINC01128 expression.ConclusionThis study indicated that ARID5B/LINC01128 was synergistically upregulated in APS, and they aggravated disease pathogenesis by enhancing the formation of the BTF3/STAT3 complex and boosting p‐STAT3‐mediated pyroptosis and apoptosis, thereby providing candidate therapeutic targets for APS.Highlights The H3K4me3 mark and chromatin accessibility at the ARID5B promoter are increased in vitro model mimicked APS. ARID5B‐mediated LINC01128 induces pyroptosis and apoptosis via p‐STAT3 by binding to BTF3. ARID5B is high‐ expressed in patients with primary APS and positively correlated with LINC01128 expression. OICR‐9429 treatment mitigates pyroptosis and related inflammation in vivo and in vitro models mimicked APS.

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Epigenetics-mediated pathological alternations and their potential in antiphospholipid syndrome diagnosis and therapy

Cited by 11 publications

References 114 publications

Interaction between Long Noncoding RNAs and Syncytin-1/Syncytin-2 Genes and Transcripts: How Noncoding RNAs May Affect Pregnancy in Patients with Systemic Lupus Erythematosus

Interaction between Long Noncoding RNAs and Syncytin-1/Syncytin-2 Genes and Transcripts: How Noncoding RNAs May Affect Pregnancy in Patients with Systemic Lupus Erythematosus

Case Report: A case of recurrent thrombosis in pediatric antiphospholipid syndrome associated with pediatric onset systemic lupus

ARID5B‐mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in β2GPI/anti‐β2GPI‐treated monocytes

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