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Genetics and Genomics of SOST: Functional Analysis of Variants and Genomic Regulation in Osteoblasts

Department of Genetics, Microbiology and Statistics, Faculty of Biology, CIBERER, IBUB, IRSJD, Universitat de Barcelona, 08028 Barcelona, Spain
Musculoskeletal Research Group, Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(2), 489;
Received: 15 December 2020 / Revised: 28 December 2020 / Accepted: 31 December 2020 / Published: 6 January 2021
(This article belongs to the Special Issue Molecular Research in Medical Genetics)
SOST encodes the sclerostin protein, which acts as a key extracellular inhibitor of the canonical Wnt pathway in bone, playing a crucial role in skeletal development and bone homeostasis. The objective of this work was to assess the functionality of two variants previously identified (the rare variant rs570754792 and the missense variant p.Val10Ile) and to investigate the physical interactors of the SOST proximal promoter region in bone cells. Through a promoter luciferase reporter assay we show that the minor allele of rs570754792, a variant located in the extended TATA box motif, displays a significant decrease in promoter activity. Likewise, through western blot studies of extracellular and intracellular sclerostin, we observe a reduced expression of the p.Val10Ile mutant protein. Finally, using a circular chromosome conformation capture assay (4C-seq) in 3 bone cell types (MSC, hFOB, Saos-2), we have detected physical interactions between the SOST proximal promoter and the ECR5 enhancer, several additional enhancers located between EVT4 and MEOX1 and a distant region containing exon 18 of DHX8. In conclusion, SOST presents functional regulatory and missense variants that affect its expression and displays physical contacts with far reaching genomic sequences, which may play a role in its regulation within bone cells. View Full-Text
Keywords: sclerostin; bone; 4C-seq; luciferase reporter assay; HBM sclerostin; bone; 4C-seq; luciferase reporter assay; HBM
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MDPI and ACS Style

Martínez-Gil, N.; Roca-Ayats, N.; Cozar, M.; Garcia-Giralt, N.; Ovejero, D.; Nogués, X.; Grinberg, D.; Balcells, S. Genetics and Genomics of SOST: Functional Analysis of Variants and Genomic Regulation in Osteoblasts. Int. J. Mol. Sci. 2021, 22, 489.

AMA Style

Martínez-Gil N, Roca-Ayats N, Cozar M, Garcia-Giralt N, Ovejero D, Nogués X, Grinberg D, Balcells S. Genetics and Genomics of SOST: Functional Analysis of Variants and Genomic Regulation in Osteoblasts. International Journal of Molecular Sciences. 2021; 22(2):489.

Chicago/Turabian Style

Martínez-Gil, Núria; Roca-Ayats, Neus; Cozar, Mónica; Garcia-Giralt, Natàlia; Ovejero, Diana; Nogués, Xavier; Grinberg, Daniel; Balcells, Susanna. 2021. "Genetics and Genomics of SOST: Functional Analysis of Variants and Genomic Regulation in Osteoblasts" Int. J. Mol. Sci. 22, no. 2: 489.

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