Cited by 40Bone Metabolism and DiseasesGenomics and Chromatin DynamicsGenetic Associations and Epidemiology

Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation

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Carey, Heather A., Hildreth, Blake E., Geisler, Jennifer A., Nickel, Mara C., Cabrera, Jennifer, Ghosh, Sankha, Jiang, Yue, Yan, Jing +11 more·2018·Bone Research

Abstract

Genome-wide association studies (GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. In this study, by integrating lineage-specific enhancers from mesenchymal and myeloid compartments with bone mineral density loci, we were able to segregate osteoblast- and osteoclast (OC)-specific functions. Specifically, in OCs, a PU.1-dependent transcription factor (TF) network was revealed. Deletion of PU.1 in OCs in mice resulted in severe osteopetrosis. Functional genomic analysis indicated PU.1 and MITF orchestrated a TF network essential for OC differentiation. Several of these TFs were regulated by cooperative binding of PU.1 with BRD4 to form superenhancers. Further, PU.1 is essential for conformational changes in the superenhancer region of Nfatc1. In summary, our study demonstrates that combining GWASs with genome-wide binding studies and model organisms could decipher lineage-specific pathways contributing to complex disease states.

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Authors
Carey, H. A., Hildreth, B. E., Geisler, J. A., Nickel, M. C., Cabrera, J., Ghosh, S., Jiang, Y., Yan, J., Lee, J., Makam, S., Young, N. A., Valiente, G. R., Jarjour, W. N., Huang, K., Rosol, T. J., Toribio, R. E., Charles, J. F., Ostrowski, M. C., & Sharma, S. M.
Affiliations
  • The Ohio State University Wexner Medical Center (US)
  • Medical University of South Carolina (US)
  • Brigham and Women's Hospital (US)
  • The Ohio State University (US)
Corresponding author
  • Ostrowski, Michael C.
  • Sharma, Sudarshana M.
Venue
Bone Research
Published
2018-03-28
Volume
6
Issue
1
Pages
8-8
ISSN
  • 2095-4700 (ISSN-L)
  • 2095-6231
OpenAlex
W2807479595
Cited by
40
References
68
Citations by year
2026: 2 · 2025: 7 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 10 · 2019: 2 · 2018: 4
FWCI
1.60
Type
journal article
Language
en
Open access
Locations
  • Bone Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Institutes of Health (T35OD010977)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR044719, 2R01AR044719-15A, K08AR062590)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
osteoclastogenesis, PU.1, enhancer variants, transcriptional regulatory networks, MITF, BRD4, super-enhancers, osteopetrosis, bone mineral density, NFATc1, osteoblast activity, genome-wide association study

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