Epigenetic regulation by p300: contributonof p300 to overall histone acetylation in vivo, and influence of p300-mediated histone acetylation on other histone modifications

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Normal levels of histone acetylation are maintained by the opposing action of two classes of enzymes, histone deacetylases and histone acetyltransferases. An imbalance of these two enzymatic activities can cause disease. Consequently, pharmacological inhibitors of histone deacetylases have emerged as promising drugs for the epigenetic therapy of various diseases. Yet, the relative contribution of individual enzymes to overall histone acetylation in vivo is unknown.The p300 protein is one of more than 15 proteins with histone acetyltransferase (AT) activity known in mammals and acts as a transcriptional co-regulator for a large number of transcription factors. We have previously shown that a reduction of p300 AT-activity specifically in B-cells of mice affects gene expression and function of mature B-cells, eventually triggering a fatal autoimmune disease. We propose to use primary and immortal B-cells specifically lacking p300 AT-activity to address the role of p300 in overall histone acetylation in vivo. In addition, we will analyse how p300-mediated histone acetylation influences other histone modifications.