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
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.
iScience. 2020 Dec 26;24(1):101989. doi: 10.1016/j.isci.2020.101989. eCollection 2021 Jan 22.
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 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.
破骨细胞（OC）对核因子κB配体（RANKL）作出反应而进行的发育，对于健康和疾病状态下的骨稳态至关重要。在破骨细胞生成过程中，BET染色质读取蛋白Brd2 - 4和与破骨细胞相关的转录因子（TFs）所引发的早期和直接的染色质调控变化尚不清楚。在此，我们证明，对RANKL作出反应时，破骨细胞的早期发育需要调控两个不同的细胞命运转录程序，即破骨细胞 - 巨噬细胞程序，其中前者激活后后者受到抑制。这两个程序均以非冗余方式受到调控，其机制是Brd2在启动子处以及Brd4在增强子/超级增强子处的染色质结合增加。Myc是RANKL诱导的首要转录因子，它与Brd2/4和Max协同作用，并通过与其他谱系相关转录因子建立负性和正性调控环来调节破骨细胞的发育。这些对破骨细胞生成转录调控的见解表明，选择性靶向Brd2/4以消除病理性破骨细胞激活具有临床潜力。
