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

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Bone Research 2018年第1期6卷 83-94页

作者： Heather A.Carey Blake E.Hildreth III jennifer a.geisler Mara C.Nickel jennifer Cabrera Sankha Ghosh Yue Jiang Jing Yan James Lee Sandeep Makam Nicholas A.Young Giancarlo R.Valiente Wael N.Jarjour Kun Huang Thomas J.Rosol Ramiro E.Toribio Julia F.Charles Michael C.Ostrowski Sudarshana M.Sharma Department of Cancer Biology and Genetics and Comprehensive Cancer Center The Ohio State University Wexner Medical Center College of Veterinary Medicine The Ohio State University Department of Biochemistry and Molecular Biology and Hollings Cancer Center Medical University of South Carolina Division of Rheumatology Immunology and Allergy Department of Medicine Brigham and Women’s Hospital and Harvard Medical School Division of Rheumatology and Immunology Department of Internal Medicine The Ohio State University Wexner Medical Center Department of Biomedical Informatics The Ohio State University Wexner Medical Center

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.

关键词： Genome-wide GWASs MITF

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