Eomes partners with PU.1 and MITF to Regulate Transcription Factors Critical for osteoclast differentiation
Eomes partners with PU.1 and MITF to Regulate Transcription Factors Critical for osteoclast differentiation
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DOI：
10.1016/j.isci.2018.12.018
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发表时间：
2019-01-25
期刊：
影响因子：
5.8
通讯作者：
Sharma, Sudarshana M.
中科院分区：
文献类型：
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作者：
Carey, Heather A.;Hildreth, Blake E., III;Sharma, Sudarshana M.
骨吸收破骨细胞（OC）来源于骨髓前体细胞（MP）。有几个转录因子与OC的分化和功能有关，然而，它们的层次结构和相互作用还不清楚。分析PU.1和MITF染色质免疫沉淀中富集的基序，结合来自分化OC的高通量测序（ChIP-seq）数据，将eomesodermin（EOMES）鉴定为在OC分化和功能关键基因处PU.1和MITF的潜在新型结合伴侣。我们能够使用免疫共沉淀和连续ChIP分析证明PU.1，MITF和EOMES在同一复合物中，并在OC基因组位点处作为复合物存在。此外，在MP中的EOMES敲低导致与体外和体内OC分化和功能降低相关的骨硬化症。虽然EOMES与胚胎发育和其他造血谱系有关，但这是第一项证明骨髓室需要EOMES的研究。
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.