In eukaryotes, the switch between alternative developmental pathways is mainly attributed to a switch in transcriptional programs. A major mode in this switch is the transition between histone deacetylation and acetylation. In budding yeast, early meiosis-specific genes (EMGs) are repressed in the mitotic cell cycle by active deacetylation of their histones. Transcriptional activation of these genes in response to the meiotic signals (i.e., glucose and nitrogen depletion) requires histone acetylation. Here we follow how this regulated switch is accomplished, demonstrating the existence of two parallel mechanisms. ( Repression and regulated expression of genes by histone deacetylases (HDACs) and histone acetyltransferases (HATs) play pivotal roles in the well-being of all eukaryotic organisms. These processes are involved in the regulation of transcription, cell cycle progression, differentiation, and the development of specific tumors, as well as in controlling the life span of organisms (8, 10). Repression of specific genes is mediated by the recruitment of the HDAC complex to promoters following association with specific DNA-binding proteins (28). In addition, recruitment of HDACs to many promoters via a nontargeted, unknown mechanism leads to global deacetylation (44). A vast amount of information is emerging on repression and activation by the HDAC and HAT enzymes, but little is known about the mechanism(s) regulating the switch between deacetylation and acetylation.

Interferon consensus sequence-binding protein (ICSBP) is a member of the interferon regulatory factors (IRF) that has a pivotal role in mediating resistance to pathogenic infections in mice and in promoting the differentiation of myeloid cells. ICSBP exerts some of its transcriptional activities via association with other factors that enable its binding to a variety of promoters containing DNA composite elements. These interactions are mediated through a specific COOH-terminal domain termed IAD (IRF association domain). To gain a broader insight of the capacity of ICSBP to interact with other factors, yeast two-hybrid screens were performed using ICSBP-IAD as a bait against a B-cell cDNA library. Trip15 was identified as a specific interacting factor with ICSBP in yeast cells, which was also confirmed by in vitro glutathione S-transferase pull-down assays and by coimmunoprecipitation studies in COS7 cells. Trip15 was recently identified as a component of the COP9/ signalosome (CSN) complex composed of eight evolutionary conserved subunits and thus termed CSN2. This complex has a role in cell-signaling processes, which is manifested by its associated novel kinase activity and by the involvement of its subunits in regulating multiple cell-signaling pathways and cell-cycle progression. We show that in vitro association of ICSBP with the CSN leads to phosphorylation of ICSBP at a unique serine residue within its IAD. The phosphorylated residue is essential for efficient association with IRF-1 and thus for the repressor activity of ICSBP exerted on IRF-1. This suggests that the CSN has a role in integrating incoming signals that affect the transcriptional activity of ICSBP. Interferon (IFN)1 regulatory factors (IRFs) constitute a family of nine cellular transcription factors that share high homology at the first 115 amino acids which comprise the DNAbinding domain and therefore bind to similar DNA elements. These factors mediate numerous biological activities such as, anti-viral activity, IFN signaling, and immunomodulation (1, 2). IRFs are expressed in many cell types and tissues except for IFN consensus sequence-binding protein (ICSBP, also termed IRF-8) and IRF-4, which are expressed specifically in immune cells. IRFs act as transcriptional repressor or activator and the current data suggest that they harbor dual function. This dual functionality is in part due to interactions with different transcription factors resulting in the ability to interact with various promoters leading to alteration in transcriptional activities, i.e. repression or activation (for review, see Ref.