Eomes partners with PU.1 and MITF to Regulate Transcription Factors Critical for osteoclast differentiation

Heather A Carey; Blake E Hildreth 3rd; Devadoss J Samuvel; Katie A Thies; Thomas J Rosol; Ramiro E Toribio; Julia F Charles; Michael C Ostrowski; Sudarshana M Sharma

doi:10.1016/j.isci.2018.12.018

Eomes partners with PU.1 and MITF to Regulate Transcription Factors Critical for osteoclast differentiation

iScience. 2019 Jan 25:11:238-245. doi: 10.1016/j.isci.2018.12.018. Epub 2018 Dec 27.

Authors

Heather A Carey¹, Blake E Hildreth 3rd², Devadoss J Samuvel³, Katie A Thies⁴, Thomas J Rosol⁵, Ramiro E Toribio⁶, Julia F Charles⁷, Michael C Ostrowski⁸, Sudarshana M Sharma⁹

Affiliations

¹ Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
² Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
³ Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
⁴ Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA.
⁵ College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
⁶ College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.
⁷ Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA. Electronic address: ostrowsk@musc.edu.
⁹ Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Biochemistry and Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Hollings Cancer Center, 86 Jonathan Lucas St, Charleston, SC 29425, USA. Electronic address: sharmas@musc.edu.

Abstract

Bone-resorbing osteoclasts (OCs) are derived from myeloid precursors (MPs). Several transcription factors are implicated in OC differentiation and function; however, their hierarchical architecture and interplay are not well known. Analysis for enriched motifs in PU.1 and MITF chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) data from differentiating OCs identified eomesodermin (EOMES) as a potential novel binding partner of PU.1 and MITF at genes critical for OC differentiation and function. We were able to demonstrate using co-immunoprecipitation and sequential ChIP analysis that PU.1, MITF, and EOMES are in the same complex and present as a complex at OC genomic loci. Furthermore, EOMES knockdown in MPs led to osteopetrosis associated with decreased OC differentiation and function both in vitro and in vivo. Although EOMES is associated with embryonic development and other hematopoietic lineages, this is the first study demonstrating the requirement of EOMES in the myeloid compartment.

Keywords: Biological Sciences; Cell Biology; Developmental Biology; Omics.

Abstract

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