Transcription factor Fra-1 reprograms androgen receptor chromatin binding and super-enhancers in osteoblast differentiation.

Transcriptional regulation by coregulators and other proteins is essential for osteoblast differentiation. Bone density maintenance requires tissue-specific androgen and androgen receptor (AR)-regulated signaling in osteoblasts. However, the transcriptional mechanisms through which androgens exert specific effects on osteoblasts remain unclear. Here, to explore androgen signaling in osteoblastic cells, we investigated comprehensive AR-binding sites by using chromatin immunoprecipitation and sequencing (ChIP-seq) analysis. We observed that the transcription factor (TF) Fra-1, an important player for osteoblast physiology, modulates epigenetic states to determine the AR cistrome and osteoblastic cell differentiation. The binding of Fra-1 to specific genomic regions in human osteoblastic cells facilitates the binding of AR to regulatory sequences, leading to active transcription. We demonstrated that the super-enhancers encoding critical developmental factors in osteoblastic cells overlapped with osteoblastic cell-specific AR-binding sites. Of note, overexpression of Fra-1 in neuronal cells, which are derived from other tissues with low baseline Fra-1 expression, we observed that Fra-1 overexpression facilitates the formation of super-enhancers associated with osteoblastic features, including the RUNX2 and TGF-β signaling pathways, by altering comprehensive histone modifications and the AR cistrome. Thus, we propose that interaction with critical transcription factors for osteoblastic cell function can govern the androgen response and epigenetic regulation involved in bone differentiation. The present findings significantly advance our understanding of sex steroid-mediated regulation of bone homeostasis.