Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development [ATAC-seq]

Osteoclast development in response to RANKL is critical for bone homeostasis in health and in disease e.g., osteoporosis and cancer. The early and direct chromatin regulatory changes imparted by BET proteins Brd2-4 and osteoclast-affiliated transcription factors (TF) during osteoclastogenesis are not known. Here we show that as early as 4h post-RANKL, osteoclast development entails regulation of two alternative cell fate transcriptional programs, osteoclast vs. macrophage, with repression of the latter following activation of the former. Pharmacological inhibition shows that this requires increased chromatin binding in a non-redundant manner of Brd2 at promoters and Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, is predicted to regulate early regulatory events in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TF. These novel insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate aberrant OC activation. Overall design: Monocyte-derived cell line induced to differentiate to OC by addition of RANKL (50ng/ml). The effect of the BET inhibitor (Ibet-500nM) was studied alone or in combination with RANKL. ATAC libraries were produced after 4 hrs incubation.