Analysis of the "de novo" chromatin opening induced by C/EBPß

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In eukaryotic cells DNA is associated with histones and exists as a compact structure, the chromatin. The activation of a gene is accompanied by local alterations of the chromatin structure making regulatory regions of the gene accessible for regulatory proteins. The mechanisms of the chromatin-remodeling have been studied in great detail, however, the initial step of opening compacted chromatin structures during the activation of a gene is only poorly understood at present. So-called “pioneer-factors” are assumed to somehow recognize the relevant regions in compact chromatin but how they initiate the opening of the compact chromatin structure has not been studied in much detail because of few of such factors have been identified. The variant histone H3.3 has currently also attracted a lot of attention because it is specifically incorporated into active chromatin regions and appears to play an important role in epigenetic mechanisms, such as epigenetic memory. Our recent work has provided us with an experimental system to study both of these processes, initial chromatin remodelling and H3.3 deposition, and establish the causal relationship between them. Using the chicken mim-1 gene as a model system we have shown that the transcription factor C/EBPβ can act as a pioneer factor and initiate „de novo“ remodelling of silent chromatin at a myeloid-specific enhancer. Furthermore, we have observed that C/EBPβ interacts with the H3.3-specific histone chaperone Hira and induces H3.3 deposition at the mim-1 enhancer, raising the intriguing possibility that both events are linked. In this research project we would like to investigate the novel functions of C/EBPβ in chromatin opening and H3.3 deposition in detail, in order to understand the mechanistic basis and causal relationship of both processes. We expect that this will not only extend our knowledge of the function of C/EBPβ but will also be of general relevance by providing novel insight into the mechanisms that are responsible for initiating chromatin remodelling in silent chromatin and into the role histone H3.3 in this process.