Genomics to Genetics: EOMES is a novel partner of MITF-PU.1 regulated transcriptome in osteoclast differentiation
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Date
2016-05
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The Ohio State University
Abstract
Bone remodeling is a continuous process regulated by bone-forming cells, osteoblasts, and bone-degrading cells, osteoclasts. Osteoclasts are derived from myeloid precursors. Increased differentiation and activation of osteoclasts offsets the balance of bone remodeling, causing the painful bone degradation associated with diseases such as osteoporosis, rheumatoid arthritis, and bone metastasis in cancer patients.
Osteoclast differentiation is brought about by an orchestrated transcription program in response to micro-environmental signaling. The full extent of this transcription factor network is not understood. Two transcription factors, MITF and PU.1, have been found to jointly regulate the transcription of many genes critical to the differentiation of myeloid precursor cells to osteoclasts. Through the use of chromatin immunoprecipitation coupled with high throughput sequencing (ChIP-Seq), we identified the genomic areas in developing osteoclasts enriched for MITF/PU.1 binding. Motif analysis revealed that 38% of these areas also included binding sites for the T-box transcription factor EOMES. Included in these sites were members of the complex transcription factor network governing osteoclast differentiation, such as NFATC1 and C-FOS.
To evaluate the physiological significance of transcription factor EOMES, we developed a myeloid specific knockout mouse model of EOMES. These mice had an osteopetrotic phenotype caused by reduced osteoclast differentiation and activity. These results were explained by a decrease in the expression of genes necessary for osteoclast differentiation, including Nfatc1. Therefore, we concluded that EOMES is another crucial transcription factor in early osteoclast differentiation. Understanding the intricate mechanisms controlling osteoclast differentiation is important for creating targets for therapeutic treatments of bone-related ailments.
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Keywords
osteoclast, EOMES, MITF, PU1, transcription factor, osteoclast differentiation