Role of Sox2 in the direct lineage reprogramming of astroglia into neurons

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Our studies during the last funding period have demonstrated that immature astroglia can be completely and stably lineage reprogrammed into functional neurons by a single neurogenic transcription factor (TF). In contrast, in more mature astroglia single neurogenic TFs fail to induce reprogramming. However, proneural gene-iduced reprogramming success can be greatly enhanced by co-expression of Sox2, a TF essential for pluripotency reprogramming as well as embryonic and neural stem cell maintenance. In the present proposal we aim at obtaining insights into the molecular mechanisms underlying the Sox2-mediated enhancement of astroglia-to-neuron lineage conversion by analyzing changes in the astrocyte transcriptome in response to Sox2. Furthermore we plan to identify binding partners of Sox2 in astrocytes by immunoprecipitation followed by mass spectrometry and to study their binding to putative Sox2 binding sites in promoter regions of identified Sox2 target genes in astrocytes by chromatin immunoprecipitation. Given the suggested programmatic role of chromatin remodelers during developmental transitions we finally will assess how the brahma-associated factor (BAF) complex differs between astrocytes and other cells and whether its composition changes with maturation. On basis of this data we will examine whether modifying the BAF complex composition in astrocytes towards either an embryonic stem cell- or neural precursorspecific state facilitates direct lineage reprogramming of astrocytes into neurons by proneural genes.