| All multicellular organisms utilize precise spatiotemporal gene expression programs to execute their development and normal homeostasis. The virus-inducible interferon β (IFN-β) enhancer is the best characterized example of how a specific external cue, such as virus, can elicit a transient burst of IFN-β gene expression in an infected cell to protect adjacent cells within a multicellular organism from the effects of subsequent viral infection. Interestingly, since the effects of prolonged IFN-β expression are detrimental to the host organism, the inducible enhancer must precisely specify both upregulation and shutoff of IFN-β transcription. All of this information is encoded by a ∼65 base pair DNA element recognized by three families of transcription factors (NF-κB, ATF-2/c-JUN, and IRFs) that, with the help of the architectural factor HMG I(Y), assemble into a higher-order nucleoprotein structure termed the enhanceosome.; The IFN-β enhanceosome is a highly dynamic structure that both activates and eventually attenuates gene expression by directing a specific program of coactivator recruitment to the enhancer DNA. Two of these coactivators, CBP and GCN5, bear an intrinsic acetyltransferase activity that allows them to catalyze histone acetylation, which has been shown to play a causal role in transcriptional regulation. In addition to histones, CBP and GCN5 acetylate the architectural component HMG I(Y) on distinct lysine residues, causing opposite effects on IFN-β transcription. Whereas acetylation by GCN5 plays a role in activation, acetylation by CBP shuts off IFN-β gene expression. Furthermore, acetylation of HMG I(Y) initially by GCN5 prevents acetylation by CBP and thus avoids premature termination during the activation phase of virus-induced gene expression. Interestingly, ordered recruitment of GCN5 and CBP is directed by discrete transformations within the enhanceosome, which results in sequential acetylation of HMG I(Y) on the IFNβ enhancer in vivo. Eventually, however, HDAC4 is recruited by the enhanceosome and reverses the effects of HMG I(Y) acetylation by GCN5, thus allowing CBP to turn off gene expression. Therefore, HMG I(Y) acetylation coordinates the virus-inducible IFN-β transcriptional switch by shifting the equilibrium between enhanceosome assembly and disassembly and may provide a paradigm for the control of inducible gene expression in multicellular organisms. |
