Correlation Engine 2.0
Clear Search sequence regions


  • alleles (4)
  • biosynthesis (2)
  • CAPNS2 (1)
  • CDKN2B (8)
  • COL4A1 (1)
  • collagen (7)
  • disease risk (1)
  • dna sequence (1)
  • extracellular matrix (1)
  • fibroblasts (5)
  • gene (9)
  • gingiva (1)
  • humans (2)
  • NFKB (1)
  • regulates (1)
  • represses (1)
  • research (1)
  • rna (5)
  • rs10757278 (3)
  • stat1 (2)
  • understand (1)
  • Sizes of these terms reflect their relevance to your search.

    The long noncoding RNA CDKN2B-AS1 harbors a major coronary artery disease risk haplotype, which is also associated with progressive forms of the oral inflammatory disease periodontitis as well as myocardial infarction (MI). Despite extensive research, there is currently no broad consensus on the function of CDKN2B-AS1 that would explain a common molecular role of this lncRNA in these diseases. Our aim was to investigate the role of CDKN2B-AS1 in gingival cells to better understand the molecular mechanisms underlying the increased risk of progressive periodontitis. We downregulated CDKN2B-AS1 transcript levels in primary gingival fibroblasts with LNA GapmeRs. Following RNA-sequencing, we performed differential expression, gene set enrichment analyses and Western Blotting. Putative causal alleles were searched by analyzing associated DNA sequence variants for changes of predicted transcription factor binding sites. We functionally characterized putative functional alleles using luciferase-reporter and antibody electrophoretic mobility shift assays in gingival fibroblasts and HeLa cells. Of all gene sets analysed, collagen biosynthesis was most significantly upregulated (Padj=9.7 × 10- 5 (AUC > 0.65) with the CAD and MI risk gene COL4A1 showing strongest upregulation of the enriched gene sets (Fold change = 12.13, Padj = 4.9 × 10- 25). The inflammatory "TNFA signaling via NFKB" gene set was downregulated the most (Padj=1 × 10- 5 (AUC = 0.60). On the single gene level, CAPNS2, involved in extracellular matrix organization, was the top upregulated protein coding gene (Fold change = 48.5, P < 9 × 10- 24). The risk variant rs10757278 altered a binding site of the pathogen responsive transcription factor STAT1 (P = 5.8 × 10- 6). rs10757278-G allele reduced STAT1 binding 14.4% and rs10757278-A decreased luciferase activity in gingival fibroblasts 41.2% (P = 0.0056), corresponding with GTEx data. CDKN2B-AS1 represses collagen gene expression in gingival fibroblasts. Dysregulated collagen biosynthesis through allele-specific CDKN2B-AS1 expression in response to inflammatory factors may affect collagen synthesis, and in consequence tissue barrier and atherosclerotic plaque stability. © 2024. The Author(s).

    Citation

    Weiwei Shi, Jiahui Song, January Mikolaj Weiner, Avneesh Chopra, Henrik Dommisch, Dieter Beule, Arne S Schaefer. lncRNA CDKN2B-AS1 regulates collagen expression. Human genetics. 2024 Jul;143(7):907-919

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 38833008

    View Full Text