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.

Robust and rapid induction of interferon-␤ (IFN-␤) in monocytes after pathogenic stimulation is a hallmark of innate immune responses. Here, we reveal the molecular mechanism underlying this key property that is exclusive to human blood monocytes. We found that IFN-␤ was produced rapidly in primary human monocytes as a result of cooperation between the myeloid-specific transcription factor IRF8 and the ubiquitous transcription factor IRF3. Knockdown of IRF8 in monocytes abrogated IFN-␤ transcription, whereas reintroduction of IRF8 into the IRF8 ؊/؊ 32Dcl3 murine myeloid cell line reinstated IFN-␤ transcription. Moreover, we provide evidence that IRF8 constitutively binds to the ETS/IRF composite element of the IFN-␤ promoter region together with PU.1 in vivo. Furthermore we uncovered a requirement for IRF3, a master regulator of IFN-␤ production, as a previously un-indentified interaction partner of IRF8. We mapped the protein- IntroductionProduction of interferon-␤ (IFN-␤) by the host is an essential first line of defense against both viral and nonviral pathogens. [1][2][3] As well as its involvement in innate immunity, IFN-␤ is an important initiator and modulator of the adaptive immune response. [4][5][6] For example, IFN-␤ influences the differentiation, maturation, and migration of dendritic cells. 7 In addition, it regulates antibody production and antigen-mediated apoptosis of B cells, 8 alongside promoting the generation of CD4 ϩ Th1 responses, 9 and the expansion of antigen-specific CD8 ϩ T cells. 10 Interestingly, Stockinger et al have recently demonstrated that IFN-␤ production contributes to Listeria monocytogenes-induced lethality in mice. 11 As such, IFN-␤ seems able to induce immunopathology as well as influence the resolution of infections, thus making it important to understand the mechanisms linking pathogen stimulation of immune cells with the production of IFN-␤.IFN-␤ transcription is initiated after cellular recognition of pathogen-associated molecular patterns by pattern recognition receptors. 12 Many cell types express IFN-␤ after microbial exposure, [13][14][15] although the underlying mechanisms vary. In murine embryonic fibroblasts, IFN-␤ induction is mediated by the activation of both IRF3 and IRF7. 16,17 In contrast, induction of IFN-␤ in murine plasmacytoid dendritic cells occurs after CpG recognition by Toll-like receptor 9 and is entirely dependent on IRF7, 18 whereas in murine macrophages transcription of IFN-␤ is dependent on IRF3 alone. 19 IRF3 is a ubiquitous cytosolic transcription factor that translocates to the nucleus on activation, 20 where it is able to induce IFN-␤ expression. However, this process takes more than 6 hours to produce detectable levels of IFN-␤ mRNA in HeLa cells, with levels peaking even later at 9 to 19 hours. 21 Monocytes are myeloid cells of the immune system that play a key role in the rapid innate response to pathogens, including the production of IFN-␤. 11,22 However, the molecular mechanisms underlying the rapid induction of IFN-␤ in monocytes hav...

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