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

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Osteoclast (OC) development, driven by nuclear factor kappa-B ligand (RANKL), is crucial for bone homeostasis.
• The precise chromatin regulatory mechanisms governing early osteoclastogenesis by BET proteins and transcription factors remain unclear.

Purpose of the Study:

• To elucidate the early chromatin regulatory changes during osteoclastogenesis mediated by BET proteins (Brd2-4) and transcription factors.
• To understand the non-redundant roles of Brd2 and Brd4 in regulating alternative cell fate transcriptional programs during OC development.

Main Methods:

• Chromatin immunoprecipitation (ChIP) assays to assess Brd2 and Brd4 binding.
• Analysis of gene expression and TF interactions using RNA sequencing and co-immunoprecipitation.

Main Results:

• RANKL induces alternative transcriptional programs for OC versus macrophage fate, with macrophage program repression.
• Brd2 binds to promoters, and Brd4 binds to enhancers/super-enhancers, regulating these programs non-redundantly.
• Myc, a key transcription factor, cooperates with Brd2/4 and Max to control OC development via regulatory loops.

Conclusions:

• Early osteoclastogenesis involves distinct roles for Brd2 and Brd4 in regulating cell fate.
• Targeting Brd2/4 offers potential therapeutic strategies for pathological OC-driven bone diseases.