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

Journal article

Caputo Galarce, V., Trasanidis, N., Xiao, X., Robinson, M. E., Katsarou, A., Ponnusamy, K., Prinjha, R. K., Smithers, N., Chaidos, A., Auner, H. W. and Karadimitris, A. (2021). Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro. iScience. 24 (1), pp. 101989-101989. https://doi.org/10.1016/j.isci.2020.101989
AuthorsCaputo Galarce, V., Trasanidis, N., Xiao, X., Robinson, M. E., Katsarou, A., Ponnusamy, K., Prinjha, R. K., Smithers, N., Chaidos, A., Auner, H. W. and Karadimitris, A.
Abstract

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.

KeywordsBiological sciences; Developmental Biology ; Bioinformatics; Omics; Transcriptomics
Year2021
JournaliScience
Journal citation24 (1), pp. 101989-101989
PublisherElsevier BV
ISSN2589-0042
Digital Object Identifier (DOI)https://doi.org/10.1016/j.isci.2020.101989
Publication dates
Print22 Jan 2021
Online25 Dec 2020
Publication process dates
Accepted25 Dec 2020
Deposited02 Feb 2021
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Open
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