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Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE160840 | GEO | 2020/11/05

REPOSITORIES: GEO

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

Project description: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.

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Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development [ATAC-seq]

Project description:Osteoclast development in response to RANKL is critical for bone homeostasis in health and in disease e.g., osteoporosis and cancer. The early and direct chromatin regulatory changes imparted by BET proteins Brd2-4 and osteoclast-affiliated transcription factors (TF) during osteoclastogenesis are not known. Here we show that as early as 4h post-RANKL, osteoclast development entails regulation of two alternative cell fate transcriptional programs, osteoclast vs. macrophage, with repression of the latter following activation of the former. Pharmacological inhibition shows that this requires increased chromatin binding in a non-redundant manner of Brd2 at promoters and Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, is predicted to regulate early regulatory events in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TF. These novel insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate aberrant OC activation.

2020-11-05 | GSE160835 | GEO

Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development [RNA-seq]

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Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development [H3K27ac ChIP-seq]

2020-11-05 | GSE160839 | GEO

Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development [BRD ChIP-seq]

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Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development [MYC_MAX ChIP-seq]

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Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development

Project description:Brd2/4 and Myc regulate alternative cell lineage programs during early osteoclast development

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