Antibody genes in B lymphocytes are assembled from multiple rearranging gene segments, enabling the immune system to protect us from a huge diversity of pathogens. Each B lymphocyte expresses only one antibody specificity on the cell surface (monospecificity), even though there is more than one allele for each antibody chain, a phenomenon termed allelic exclusion. Allelic exclusion requires asynchronous rearrangement of antibody genes combined with feedback inhibition to prevent the assembly of more than one productive allele. This proposal aims to analyze how epigenetic genome modifications influence the asynchronous rearrangements of antibody genes by defining and then altering the precise distribution of histone modifications. Further, to determine the significance of monospecificity to B lymphocyte development and function, this proposal aims to establish a novel gene-targeted mouse that expresses a diverse, but allelically included antibody repertoire. This will provide new insights as to how the immune system reacts specifically against foreign pathogens while maintaining self-tolerance. Hence, this proposal will elucidate the mechanism and importance of allelic exclusion of antibody genes in the immune system. The project will be conducted through a collaboration between the University of Erlangen-Nürnberg, Germany and the University of California, Berkeley, USA. The outcome of this proposal will improve our predictive knowledge of various human diseases including infections, cancer and autoimmune diseases, and thus support sustainable healthcare in the EU.