Regulation of genome structure and function by the transcription factor BACH2

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED


T cells coordinate immune function by differentiating into highly specialised cellular lineages that either promote or suppress immune reactions. Whereas effector T cells drive immune activation and can cause clearance of infections and cancer, regulatory T cells, dependent upon the transcription factor Foxp3, suppress their function to prevent excessive immune reactions. Stability of regulatory T cell populations is required throughout life to maintain immune homeostasis. In cancer, however, regulatory T cells suppress effector responses and their remarkable stability is a barrier to immune-mediated clearance of disease. It is important to understand how stability of regulatory T cells is programmed if new immune-based therapies that manipulate regulatory T cell stability are to be developed for a variety of disorders. This project aims to determine molecular mechanisms of regulatory T cell stability. We have recently identified a transcription factor protein, BACH2, that functions as a pervasive regulator of immune activation, promoting the formation of regulatory T cells while suppressing the differentiation and function of multiple effector lineages [1]. Genetic polymorphisms within the BACH2 locus are associated with susceptibility to numerous autoimmune and allergic diseases in humans and deletion of BACH2 in mice results in spontaneous lethal inflammation. The function of BACH2 within regulatory T cells is currently unknown. We have found that BACH2 predominantly binds the genome at enhancers and controls expression of distant genes. The proposed project will extend our understanding of the molecular and epigenetic mechanisms by which BACH2 controls the stability of regulatory T cells during homeostasis and in cancer using cutting edge mouse genetics and tumour models. This will identify new targets for development of drugs aimed at manipulating immune function in patients with autoimmunity and cancer.


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