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Cited by 158Genomics and Chromatin DynamicsBone health and osteoporosis researchGenetic Associations and Epidemiology

Genome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density

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Chesi, Alessandra, Wagley, Yadav, Johnson, Matthew E., Manduchi, Elisabetta, Su, Chun, Lu, Sumei, Leonard, Michelle E., Hodge, Kenyaita M. +4 more·2019·Nature Communications
DOI 10.1038/s41467-019-09302-xPMC PMC6425012
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Abstract

Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~ 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at ‘CPED1-WNT16’ and EPDR1 at ‘STARD3NL’, inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.

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  • 3C-derived methods have detected multitudes of enhancer-promoter loops in many human and mouse cell types.

    “These enrichment methods have detected multitudes of enhancer–promoter loops in many human and mouse cell types [243, 286–291].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [290]

    The Results section (page unavailable in our copy) reports 295,422 promoter interactions detected by Capture C in human osteoblasts and also describes a comparison with a human HepG2 cell line. It does not establish detection in many human and mouse cell types; the cited paper’s experiments described here involve human cells, not mouse cells. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The authors previously identified ING3 and EPDR1 as long-range effector genes regulated by osteoblast enhancers harboring bone mineral density GWAS SNPs at the WNT16-CPED1 and STARD3NL loci.

    “Additionally, we identified ING3 and EPDR1 as the long-range effector genes regulated by osteoblast enhancers harboring bone mineral density GWAS SNPs at the WNT16-CPED1 and STARD3NL loci, respectively20.”

    From Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicates <i>RTFDC1</i> at the <i>CASS4</i> locus (2024) · cites this paper as [20]

    The Results (Functional studies; page unavailable) identify ING3 at the WNT16-CPED1 locus and EPDR1 at the STARD3NL locus, and report interactions between their promoters and regions containing BMD GWAS proxy SNPs in osteoblasts. The Discussion also describes both as implicated genes involved in osteoblast differentiation. The paper does not establish that the interacting regions are enhancers that regulate these genes, so that causal part of the claim is stronger than the evidence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Chesi, A., Wagley, Y., Johnson, M. E., Manduchi, E., Su, C., Lu, S., Leonard, M. E., Hodge, K. M., Pippin, J. A., Hankenson, K. D., Wells, A. D., & Grant, S. F. A.
Affiliations
  • Children's Hospital of Philadelphia (US)
  • University of Michigan (US)
Corresponding author
Grant, Struan F. A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-03-19
Volume
10
Issue
1
Pages
1260-1260
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-019-09302-x
PMC
PMC6425012
OpenAlex
W2925136170
Cited by
158
References
61
Citations by year
2026: 10 · 2025: 13 · 2024: 40 · 2023: 21 · 2022: 25 · 2021: 26 · 2020: 18 · 2019: 5
FWCI
6.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Children's Hospital of Philadelphia
  • National Institutes of Health (P40OD011050)
  • National Human Genome Research Institute (R01HG010067)
  • Office of Research Infrastructure Programs, National Institutes of Health (P40OD011050)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
bone mineral density, osteoporosis, GWAS loci, effector genes, promoter interactions, chromatin interactions, open chromatin, ING3, EPDR1, WNT16, mesenchymal progenitor cells, osteoblastogenesis, adipogenesis
MeSH terms
Secreted Frizzled-Related Proteins, Adult, Cell Differentiation, Chromosome Mapping, Female, Humans, Male, Membrane Proteins, Neoplasm Proteins, Nerve Tissue Proteins, Osteoblasts, Osteogenesis, Osteoporosis, Promoter Regions, Genetic, Proto-Oncogene Proteins, Bone Density, Homeodomain Proteins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, RNA, Small Interfering, Intercellular Signaling Peptides and Proteins, Adipogenesis, Wnt Proteins, Genome-Wide Association Study, Gene Knockdown Techniques, Young Adult, Genetic Loci, Hep G2 Cells, Mesenchymal Stem Cells, Primary Cell Culture

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