Genetic analysis of cis-enhancers associated with bone mineral density and periodontitis in the gene SOST.

Avneesh Chopra, Jiahui Song, January Weiner Rd, Dieter Beule, Arne S Schaefer

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Article in PloS one, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 authors.

Avneesh ChopraDepartment of Periodontology, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité-University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.ORCID https://orcid.org/0000-0001-7706-3577

Jiahui SongDepartment of Periodontology, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité-University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

January Weiner RdCore Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany.

Dieter BeuleCore Unit Bioinformatics, Berlin Institute of Health, Berlin, Germany.

Arne S SchaeferDepartment of Periodontology, Oral Medicine and Oral Surgery, Institute for Dental and Craniofacial Sciences, Charité-University Medicine Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.ORCID https://orcid.org/0000-0001-5816-6765

Funding

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6 · The paper itself

Abstract

A haplotype block at the sclerostin (SOST) gene correlates with bone mineral density (BMD) and increased periodontitis risk in smokers. Investigating the putative causal variants within this block, our study aimed to elucidate the impact of linked enhancer elements on gene expression and to evaluate their role in transcription factor (TF) binding. Using CRISPR/dCas9 activation (CRISPRa) screening in SaOS-2 cells, we quantified disease-related enhancer activities regulating SOST expression. Additionally, in SaOS-2 cells, we investigated the influence of the candidate TFs CCAAT/enhancer-binding protein beta (CEBPB) on gene expression by antisense (GapmeR) knockdown, followed by RNA sequencing. The periodontitis-linked SNP rs9783823 displayed a significant cis-activating effect (25-fold change in SOST expression), with the C-allele containing a CEBPB binding motif (position weight matrix (PWM) = 0.98, Pcorrected = 7.7 x 10-7). CEBPB knockdown induced genome-wide upregulation but decreased epithelial-mesenchymal transition genes (P = 0.71, AUC = 2.2 x 10-11). This study identifies a robust SOST cis-activating element linked to BMD and periodontitis, carrying CEBPB binding sites, and highlights CEBPB's impact on epithelial-mesenchymal transition.

Indexed as

Bone DensityEnhancer Elements, GeneticPeriodontitisAdaptor Proteins, Signal TransducingCCAAT-Enhancer-Binding Protein-betaCell Line, TumorEpithelial-Mesenchymal TransitionGene Expression RegulationGenetic MarkersHumansPolymorphism, Single NucleotideAdaptor Proteins, Signal TransducingCCAAT-Enhancer-Binding Protein-betaCEBPB protein, humanGenetic MarkersSOST protein, human

Identifiers

PMID40127057

DOI10.1371/journal.pone.0319259

PMCPMC11932464

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