Transdifferentiation in the Cochlea

We will identify the genes regulated by TBX2 and driving IHC vs OHC differentiation, including the chain of gene-expression events leading from one cell type to the other. We also inquire whether TBX2 acts as a transcriptional activator or repressor, and whether it acts by modifying the epigenome of IHCs, either opening regulatory elements required for IHC differentiation or closing those required for OHC differentiation. To test these and alternative hypotheses, we will perform ATAC-seq on developing and mature IHCs, OHCs, and IHCs lacking TBX2 (all of which transdifferentiate into OHCs). Finally, we will identify the TBX2-binding sites in the promoters and enhancers of the genes it regulates in order to trigger and/or maintain IHC differentiation. These studies use the transdifferentiation of IHCs into OHCs (and vice versa) triggered by TBX2 missregulation as a means for elucidating the molecular mechanisms (transcriptomic and epigenomic) by which the complementary IHCs and OHCs are generated in the developing cochlea.