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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.

Original publication

DOI

10.1074/jbc.M112.413047

Type

Journal article

Journal

J Biol Chem

Publication Date

14/12/2012

Volume

287

Pages

43137 - 43155

Keywords

Acetylation, Binding Sites, CD4-Positive T-Lymphocytes, Cell Lineage, Embryonic Stem Cells, Enhancer Elements, Genetic, Genome, Human, HeLa Cells, Histone Acetyltransferases, Histone Deacetylases, Histones, Humans, Jurkat Cells, Lysine, Nuclear Proteins, Phosphorylation, Phosphoserine, Positive Transcriptional Elongation Factor B, Promoter Regions, Genetic, Protein Binding, Protein Transport, RNA Polymerase II, Transcription Factors, Transcription, Genetic