Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells

Journal article

Transcriptional elongation by RNA polymerase II (Pol II) is regulated by positive transcription elongation factor b (P-TEFb) in association with bromodomain-containing protein 4 (BRD4). We used genome-wide chromatin immunoprecipitation sequencing in primary human CD4+ T cells to reveal that BRD4 co-localizes with Ser-2-phosphorylated Pol II (Pol II Ser-2) at both enhancers and promoters of active genes. Disruption of bromodomain-histone acetylation interactions by JQ1, a small-molecule bromodomain inhibitor, resulted in decreased BRD4 binding, reduced Pol II Ser-2, and reduced expression of lineage-specific genes in primary human CD4+ T cells. A large number of JQ1-disrupted BRD4 binding regions exhibited diacetylated H4 (lysine 5 and -8) and H3K27 acetylation (H3K27ac), which correlated with the presence of histone acetyltransferases and deacetylases. Genes associated with BRD4/H3K27ac co-occupancy exhibited significantly higher activity than those associated with H3K27ac or BRD4 binding alone. Comparison of BRD4 binding in T cells and in human embryonic stem cells revealed that enhancer BRD4 binding sites were predominantly lineage-specific. Our findings suggest that BRD4-driven Pol II phosphorylation at serine 2 plays an important role in regulating lineage-specific gene transcription in human CD4+ T cells.

Authors: Zhang, W; Prakash, C; Prakash, C; Sum, C; Sum, C

• Publication status: Published
• Peer review status: Peer reviewed
• Journal: Journal of biological chemistry
• Volume: 287
• Issue: 51
• Pages: 43137-43155
• Publication date: 2012-12-01
• DOI: 10.1074/jbc.m112.413047
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Genome, Human; Nuclear Proteins; Enhancer Elements, Genetic; Positive Transcriptional Elongation Factor B; Protein Transport; Humans; Histone Acetyltransferases; Binding Sites; Phosphorylation; Histones; Histone Deacetylases; Transcription Factors; Embryonic Stem Cells; Transcription, Genetic; CD4-Positive T-Lymphocytes; Promoter Regions, Genetic; Cell Lineage; Hela Cells; Lysine; Jurkat Cells; RNA Polymerase II; Acetylation; Phosphoserine; Protein Binding