IADR Abstract Archives
BACH1 Binding Links the Genetic Risk for Severe Periodontitis With ST8SIA1
Objectives: Genome-wide association studies identified various loci associated with periodontal diseases, but assigning causal alleles remains difficult. Likewise, the generation of biological meaning underlying a statistical association has been challenging. Here, we characterized the genetic association at the gene ST8SIA1 that increases the risk for severe periodontitis in smokers.
Methods: We used CRISPR/dCas9 activation and RNA-Sequencing to identify genetic interaction partners of ST8SIA1 and to determine its function in the cell. We used reporter gene assays to identify regulatory elements at the associated SNPs and to determine effect directions and allele specific changes of enhancer activity. Antibody electrophoretic mobility shift assays proved allele specific transcription factor binding at the putative causal SNPs.
Results: We found the reported periodontitis risk gene ABCA1 as top up-regulated gene following ST8SIA1 activation. Gene set enrichment analysis showed highest effects on integrin cell surface interactions (AUC = 0.85 (q = 4.9x10-6) and cell cycle regulation (AUC) = 0.89 (q = 1.6x10-5). We identified two associated repressor elements in the introns of ST8SIA1 that bind the transcriptional repressor BACH1. The putative causative variant rs2012722 decreased BACH1 binding by 40%. We also pinpointed ST8SIA1 as the target gene of the association.
Conclusions: ST8SIA1 inhibits cell adhesion with extracellular matrix proteins and integrins, cell cycle, and enhances apoptosis. Likewise, tobacco smoke reportedly results in inhibition of cell adhesion, decrease in integrin-positive cells and cell growth. We conclude that impaired ST8SIA1 repression, independently caused by reduced BACH1 binding at the effect T-allele as well as by tobacco smoke, contribute to higher ST8SIA1 levels and in smokers who carry the effect T-allele, both factors would be additive with damaging effects on the gingival barrier integrity. The activity of ST8SIA1 is also linked with the periodontitis risk gene ABCA1.
Methods: We used CRISPR/dCas9 activation and RNA-Sequencing to identify genetic interaction partners of ST8SIA1 and to determine its function in the cell. We used reporter gene assays to identify regulatory elements at the associated SNPs and to determine effect directions and allele specific changes of enhancer activity. Antibody electrophoretic mobility shift assays proved allele specific transcription factor binding at the putative causal SNPs.
Results: We found the reported periodontitis risk gene ABCA1 as top up-regulated gene following ST8SIA1 activation. Gene set enrichment analysis showed highest effects on integrin cell surface interactions (AUC = 0.85 (q = 4.9x10-6) and cell cycle regulation (AUC) = 0.89 (q = 1.6x10-5). We identified two associated repressor elements in the introns of ST8SIA1 that bind the transcriptional repressor BACH1. The putative causative variant rs2012722 decreased BACH1 binding by 40%. We also pinpointed ST8SIA1 as the target gene of the association.
Conclusions: ST8SIA1 inhibits cell adhesion with extracellular matrix proteins and integrins, cell cycle, and enhances apoptosis. Likewise, tobacco smoke reportedly results in inhibition of cell adhesion, decrease in integrin-positive cells and cell growth. We conclude that impaired ST8SIA1 repression, independently caused by reduced BACH1 binding at the effect T-allele as well as by tobacco smoke, contribute to higher ST8SIA1 levels and in smokers who carry the effect T-allele, both factors would be additive with damaging effects on the gingival barrier integrity. The activity of ST8SIA1 is also linked with the periodontitis risk gene ABCA1.