BRD4 regulates adiponectin gene induction by recruiting the P-TEFb complex to the transcribed region of the gene

Abstract

We previously reported that induction of the adipocyte-specific gene adiponectin (Adipoq) during 3T3-L1 adipocyte differentiation is closely associated with epigenetic memory histone H3 acetylation on the transcribed region of the gene. We used 3T3-L1 adipocytes and Brd4 heterozygous mice to investigate whether the induction of Adipoq during adipocyte differentiation is regulated by histone acetylation and the binding protein bromodomain containing 4 (BRD4) on the transcribed region. Depletion of BRD4 by shRNA and inhibition by (+)-JQ1, an inhibitor of BET family proteins including BRD4, reduced Adipoq expression and lipid droplet accumulation in 3T3-L1 adipocytes. Additionally, the depletion and inhibition of BRD4 reduced the expression of many insulin sensitivity-related genes, including genes related to lipid droplet accumulation in adipocytes. BRD4 depletion reduced P-TEFb recruitment and histone acetylation on the transcribed region of the Adipoq gene. The expression levels of Adipoq and fatty acid synthesis-related genes and the circulating ADIPOQ protein level were lower in Brd4 heterozygous mice than in wild-type mice at 21 days after birth. These findings indicate that BRD4 regulates the Adipoq gene by recruiting P-TEFb onto acetylated histones in the transcribed region of the gene and regulates adipocyte differentiation by regulating the expression of genes related to insulin sensitivity.

The epigenetic reader Brd4 is required for osteoblast differentiation

“…This observation may reflect shifts in Brd4 binding from a broad and nonspecific distribution throughout the genome to highly localized interactions at active enhancers after induction of differentiation (J. E. Lee et al, ). Our finding that Brd4 binds close to Runx2 binding sites in murine MC3T3 osteoblasts corroborates previous studies with human fetal osteoblasts (Najafova et al, ) and is consistent with the broader concept that Brd4 supports cellular differentiation by cooperating with lineage‐specific transcription factors to activate transcriptional networks (Gilmour et al, ; Najafova et al, ; Sakurai et al, ).…”

“…Additionally, we show that Brd2 and Brd4 expression levels are highest early in the osteogenic differentiation time course. This pattern suggests that these epigenetic reader proteins are crucial during early osteoblast lineage commitment which is similar to findings in other cell types (J. E. Lee et al, ; Sakurai et al, ).…”

“…The same may occur in MC3T3 osteoblasts in which administration of +JQ1 may reduce expression of osteoblastic genes by removing Brd4 from their promoters. The unique ability of Brd4 to interact with RNA‐Pol II via CDK9 and the p‐TEFb complex renders it a key component of transcriptional activation (Sakurai et al, ). These findings affirm the role of Brd4 as the molecular bridge between hyper‐acetylated histone tails and the RNA transcription machinery.…”

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

“…A well‐studied BET family member, BRD4, usually recruits the P‐TEFb transcription elongation factor or other transcriptional factors or chooses modifiers of histones to promote activation of target genes at the transcriptional stage . BRD4 is crucially involved in several cellular processes, including the progression of the cell cycle, cell growth control, apoptosis and tumour initiation . BRD4 is often overexpressed and clinically associated with various human cancers via its elevation of the expression and enhancement of the oncogenic functions of major proteins in cancer, such as aldehyde dehydrogenases (ALDH) in ovarian cancer, androgen receptor (AR) and ETS‐related gene (ERG) in prostate cancer and c‐Myc in leukaemia .…”

“…16,17 BRD4 is crucially involved in several cellular processes, including the progression of the cell cycle, cell growth control, apoptosis and tumour initiation. 18 BRD4 is often overexpressed and clinically associated with various human cancers via its elevation of the expression and enhancement of the oncogenic functions of major proteins in cancer, such as aldehyde dehydrogenases (ALDH) in ovarian cancer, androgen receptor (AR) and ETS-related gene (ERG) in prostate cancer and c-Myc in leukaemia. 19,20 BRD4 was shown to regulate PTEN and the PI3K/AKT pathway.…”