GATA4 regulates estrogen receptor-alpha-mediated osteoblast transcription.

Estrogens regulate osteoblast differentiation and mineralization. We identified GATA4 as a transcription factor expressed in osteoblasts and directly regulated by 17 beta-estradiol in this cell type but not in breast cancer cells, another estrogen-responsive tissue. Chromatin immuno-precipitation sequencing (chromatin immunoprecipitation sequencing) reveals that estrogen receptor alpha (ER alpha) binds to chromatin near GATA4 at five different enhancers. GATA4 and ER alpha are both recruited to ER alpha binding sites near genes that are specifically expressed in osteoblasts and control osteoblast differentiation. Maximal binding of GATA4 precedes ER alpha binding, and GATA4 is necessary for histone 3 lysine 4 dimethylation at ER alpha binding sites, suggesting that GATA4 is a pioneer factor for ER alpha. As such, knockdown of GATA4 reduced recruitment of ER alpha to DNA. Our study illustrates that GATA4 is a pioneer factor for ER alpha recruitment to osteoblast-specific enhancers. (Molecular Endocrinology 25: 1126-1136, 2011)