Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro

• Published in: iScience Vol. 24; no. 1; p. 101989
• Main Authors: Caputo, Valentina S., Trasanidis, Nikolaos, Xiao, Xiaolin, Robinson, Mark E., Katsarou, Alexia, Ponnusamy, Kanagaraju, Prinjha, Rab K., Smithers, Nicholas, Chaidos, Aristeidis, Auner, Holger W., Karadimitris, Anastasios
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.01.2021; Elsevier
• Subjects: Bioinformatics; Biological Sciences; Developmental Biology; Omics; Transcriptomics; Biological Sciences; Developmental Biology; Transcriptomics; Bioinformatics; Omics
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101989

Osteoclast (OC) development in response to nuclear factor kappa-Β ligand (RANKL) is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and OC-affiliated transcription factors (TFs) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early OC development entails regulation of two alternative cell fate transcriptional programmes, OC vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates OC development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TFs. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation. [Display omitted] •Upregulation of osteoclast lineage commitment TFs occurs <24hr after RANKL stimulation•Enhanced binding of Brd2&4, but not Brd3, is required for osteoclast fate commitment•Brd2&4 occupancy is associated with super-enhancer reprogramming and TF rewiring•Myc is the epicenter of the TF regulatory network driving osteoclastogenesis Biological Sciences; Developmental Biology; Bioinformatics; Omics; Transcriptomics