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Main Title: BACH1 Binding Links the Genetic Risk for Severe Periodontitis with ST8SIA1
Author(s): Chopra, Avneesh
Mueller, R.
Weiner, J.
Rosowski, J.
Dommisch, Henrik
Grohmann, E.
Schaefer, A.S.
Type: Article
Abstract: 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. 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 single-nucleotide polymorphisms (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. We found the reported periodontitis risk gene ABCA1 as the top upregulated gene following ST8SIA1 activation. Gene set enrichment analysis showed highest effects on integrin cell surface interactions (area under the curve [AUC] = 0.85; q = 4.9 × 10−6) and cell cycle regulation (AUC = 0.89; q = 1.6 × 10−5). We identified 2 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. ST8SIA1 inhibits cell adhesion with extracellular matrix proteins, integrins, and cell cycle, as well as enhances apoptosis. Likewise, tobacco smoke reportedly results in an inhibition of cell adhesion and a 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, contributes 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.
Subject(s): periodontal diseases
tobacco smoke
reporter genes
extracellular matrix
transcription factors
Issue Date: 1-Jan-2022
Date Available: 5-Jan-2022
Language Code: en
DDC Class: 610 Medizin und Gesundheit
Journal Title: Journal of Dental Research
Publisher: SAGE
Volume: 101
Issue: 1
Publisher DOI: 10.1177/00220345211017510
Page Start: 93
Page End: 101
EISSN: 1544-0591
ISSN: 0022-0345
TU Affiliation(s): Fak. 3 Prozesswissenschaften » Inst. Biotechnologie » FG Medizinische Biotechnologie
Appears in Collections:Technische Universität Berlin » Publications

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