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DNA hypermethylation of MED1 and MED23 as early diagnostic biomarkers for unsolved issues in atrial fibrillation

ABSTRACT: Although evidence supports that aberrant DNA methylation exists in the hearts of patients with atrial fibrillation (AF), epigenetic phenomena underlying the onset and progression of AF are not yet fully understood. We therefore investigated DNA methylome changes in circulating CD4+ T cells isolated from AF patients and healthy subjects (HS), enrolled in the ongoing DIANA clinical trial (NCT04371809), by using reduced-representation bisulfite sequencing (RRBS). Network analysis was applied to investigate differential DNA methylation profiles and functional effects. An atrial-specific PPI network revealed 18 hub differentially methylated genes (DMGs). ROC curve analysis revealed that DNA methylation levels of CDK5R1 (AUC = 0.755; P = 0.049), HSPG2 (AUC = 0.768; P = 0.038), WDFY3 (AUC = 0.782; P = 0.029), USP49 (AUC = 0.755; P = 0.049) and GSE1 (AUC = 0.755; P = 0.049), AIFM1 (AUC = 0.764; P = 0.041), CDK5RAP2 (AUC = 0.809; P = 0.017), COL4A1 (AUC = 0.864; P<0.001), SEPT8 (AUC = 0.900; P<0.001), PFDN1 (AUC = 0.900; P<0.01), and ACOT7 (AUC = 0.777; P = 0.032) provided a good performance on predicting the presence AF. Transcriptional profiling of the hub DMGs provided a significant overexpression of PSDM6 (P=0.004), TFRC (P=0.01), CDK5R1 (P<0.001), HSPG2 (P=0.01), WDFY3 (P<0.001), USP49 (P=0.004), and GSE1 (P=0.021) in AF patients vs HS. CDK5R1, GSE1, HSPG2, and WDFY3 resulted the best discriminatory genes both at methylation and gene expression level. Our results provide putative diagnostic biomarkers with the potential to advance precision medicine in AF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240191 | GEO | 2025/07/14

REPOSITORIES: GEO

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Project description:Background: Lung cancer, particularly lung adenocarcinoma, remains one of the most lethal malignancies globally. Identifying aberrant molecular pathways and potential therapeutic targets is pivotal for improving patient outcomes. This study focused on the role of GSE1 (genetic suppressor element 1) in lung adenocarcinoma, elucidating its interaction mechanisms and downstream effects. Objectives: 1. Determine the expression levels of GSE1 in lung adenocarcinoma tissues and its implication on cancer cell behaviors. 2. Investigate the effects of GSE1 depletion on the proliferation and migration capabilities of A549 and H1299 lung adenocarcinoma cell lines. 3. Elucidate the potential cellular partners of GSE1, with a particular focus on its interaction with histone deacetylase 1 (HDAC1) and the broader BRAF-HDAC complex (BHC). 4. Analyze the transcriptomic changes following GSE1-knockdown in A549 cells to pinpoint its broad molecular influence. 5. Examine the possible cooperative role of GSE1 and HDAC1 in modulating the expression of significant genes, especially the tumor suppressor gene KLF6. Methods: GSE1 expression was assessed in lung adenocarcinoma tissues and correlated with cell behaviors. The effects of GSE1 depletion were studied in A549 and H1299 cells. Immunoprecipitation assays were utilized to confirm GSE1's interactions. Transcriptomic analysis identified differentially expressed genes post-GSE1-knockdown, with a focus on genes harboring HDAC1 binding sites. The relationship between GSE1 and KLF6 expression was verified using RT-qPCR and western blotting. Results: GSE1 was found to be upregulated in lung adenocarcinoma. Its depletion inhibited proliferation and migration in both A549 and H1299 cells. GSE1 was demonstrated to interact with HDAC1 and other BHC components. Following GSE1-knockdown, 207 genes were upregulated and 159 were downregulated, with 140 genes showcasing HDAC1 binding sites. Among these genes, GSE1 was revealed to inhibit the transcription of the tumor suppressor gene KLF6. Conclusion: GSE1 plays a central role in promoting non-small cell lung cancer progression, potentially through its cooperation with HDAC1. This interaction appears to downregulate KLF6 expression, highlighting a novel molecular pathway that can be targeted for therapeutic interventions in lung adenocarcinoma.

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DNA hypermethylation of MED1 and MED23 as early diagnostic biomarkers for unsolved issues in atrial fibrillation

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