Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro
Valentina S. Caputo,
Nikolaos Trasanidis,
Xiaolin Xiao,
Mark E. Robinson,
Alexia Katsarou,
Kanagaraju Ponnusamy,
Rab K. Prinjha,
Nicholas Smithers,
Aristeidis Chaidos,
Holger W. Auner,
Anastasios Karadimitris
Affiliations
Valentina S. Caputo
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Nikolaos Trasanidis
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Xiaolin Xiao
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Mark E. Robinson
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Alexia Katsarou
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK; Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK
Kanagaraju Ponnusamy
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
Rab K. Prinjha
Medicines Research Centre, GlaxoSmithKline, Stevenage, UK
Nicholas Smithers
Medicines Research Centre, GlaxoSmithKline, Stevenage, UK
Aristeidis Chaidos
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK; Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK
Holger W. Auner
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK; Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK
Anastasios Karadimitris
Hugh & Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK; Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust, London, UK; Corresponding author
Summary: 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.
