Molecular biology of the dimerization functions of the androgen receptor

The androgen receptor (AR: NR3C4) is a transcription factor which plays a central role in the development and maintenance of the male phenotype. This is illustrated by the many AR mutations that have been described in androgen insensitivity syndrome patients. While most of these mutations affect known AR functions like ligand, DNA or co-activator binding, some remained unexplained. We recently described a detailed map of the dimerization interface of the ligandbinding domain (LBD) in which over 40 of these formerly unexplained mutations are situated. The here presented project aims to define the in vivo implications of LBD dimer-disrupting mutations. We will develop the first rodent model in which a specific function of the AR can be knocked in, in an inducible way. This will allow the in vivo study of the impact of the mutation on transcription in adult tissues. There are three ways in which the AR can dimerize: via the DNA-binding domain, via interactions between the amino- and carboxyterminal domains and via this LBD surface. The second work package will use STARRseq methodology to define the role of each of these three interfaces during AR transactivation and DNA recognition. Ultimately, we will integrate the data from the in vivo and in vitro work to link receptor dimerization modes with tissue-specific AR functioning at the chromatine level.