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

Heather A. Carey, Blake E. Hildreth, 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

*此作品的通信作者

研究成果: Article同行評審

31 引文 斯高帕斯(Scopus)

摘要

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.

原文English
文章編號8
期刊Bone Research
6
發行號1
DOIs
出版狀態Published - 1 12月 2018

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