Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro
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Published version
Author(s)
Type
Journal Article
Abstract
Osteoclast development in response to 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 osteoclast-affiliated transcription factors (TF) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early osteoclast development entails regulation of two alternative cell fate transcriptional programmes, osteoclast 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 osteoclast development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TF. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation.
Date Issued
2021-01-22
Online Publication Date
2021-01-07T09:28:43Z
Date Acceptance
2020-01-21
ISSN
2589-0042
Publisher
Elsevier BV
Start Page
1
End Page
31
Journal / Book Title
iScience
Volume
24
Issue
1
Copyright Statement
© 2021 The Authors. This Pre-proof version is available open access under a CC-BY-NC-ND Attribution Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor
Cancer Research UK
Identifier
https://www.sciencedirect.com/science/article/pii/S258900422031186X?via%3Dihub
Grant Number
C41494/A29035
Subjects
Bioinformatics
Biological Sciences
Developmental Biology
Omics
Transcriptomics
Publication Status
Published
Article Number
101989
Date Publish Online
2020-12-26