Bromodomain-containing Protein 4 (BRD4) Regulates RNA Polymerase II Serine 2 Phosphorylation in Human CD4+ T Cells

Abstract

Background: BRD4 interacts with P-TEFb, which regulates Pol II elongation. Results: Disruption of BRD4 binding by JQ1 resulted in reduced Pol II Ser-2 in CD4ϩ T cells. Conclusion: BRD4 affects Pol II Ser-2 phosphorylation at a subset of lineage-specific active genes in primary human CD4ϩ T cells. Significance: BRD4 binding may represent a means of identifying active promoters and lineage-specific enhancer elements.

GC skew defines distinct RNA polymerase pause sites in CpG island promoters

“…The profile of ongoing transcription (GRO-seq) from normal breast epithelia (MCF10A) (Kim et al 2013) and fetal lung fibroblast (IMR90) (Core et al 2008), and ChIP-seq for serine-5 phosphorylated Pol II from CD4+ T-cells (Zhang et al 2012) was examined at CGI-associated promoters using the same sort order (distance from the TSS to the 3 ′ CGI edge) and class distinctions derived for MCF7 cells in Figure 1C. Interestingly, the position of the dominant pause for individual genes was consistent across multiple cell types (Fig.…”

“…For MCF10A cells, the following data set was used: GRO-seq (ERX016683) (Kim et al 2013). For CD4+ T cells, the following data sets were used: ChIP-seq of Pol IIS5 (GSM1022949) (Zhang et al 2012) and BRD4 (GSM823378) (Zhang et al 2012). For HeLa cells, the following data sets were used: ChIP-seq of NELFA (GSM1280296) ) and the SUPT5H component of DSIF (GSM1280295) .…”

“…Enhancers are cis-acting regulatory elements that control transcription from a distance through the formation of contacts between the enhancer-bound transcription factors and promoter-bound Pol II and the looping out of intervening chromatin (Kagey et al 2010b). BRD4 and components of the P-TEFb complex have been shown to colocalize with elongating (serine-2-phosphorylated) Pol II at both the promoters and enhancers of active genes, and inhibition of either suppresses not only elongation of promoter-derived mRNAs but also that of noncoding "eRNAs" arising at distal enhancers (Zhang et al 2012;Anand et al 2013;Liu et al 2013;Loven et al 2013;Kanno et al 2014). In addition, long-range chromatin looping interactions have been shown to correlate with paused Pol II during Drosophila development (Ghavi-Helm et al 2014).…”

Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma

“…13 Similar to other bromodomain proteins, such as BRD2 and BRD3, BRD4 has also been shown to associate with chromatin via interaction with different histone acetylation marks, such as H4K5, H4K8, H4K12, H3K9, H3K14, H4K16, and H3K27. [13][14][15][16][17] Of these, BRD4 bound H3K27Ac sites have been associated with very high gene activity. 16 Emerging data links disruption of super-enhancers with inhibitory oncogene transcription that often exhibits high levels of BRD4 occupancy at nearby enhancer/ super-enhancer regions, such as c-Myc in haematopoietic malignancies.…”

“…1). 15 Control regions were chosen as 5000 base pair (bp) upstream and downstream of the putative c-Myc super-enhancer region. It has been shown that super-enhancers are correlated with higher levels of occupancy of both H3K27Ac and BRD4.…”