The field of chromatin biology has recently undergone a tremendous resurgence in interest. This has mainly been fueled by the knowledge that factors responsible for modifying and remodeling nucleosomes are essential for ensuring the proper repertoire of gene expression during both development and adulthood. One class of factors uses the energy of ATP to modify the placement of histone octamers on DNA. In the regulatory regions of genes this placement can directly influence gene expression levels by providing or denying access to RNA Pol I1. The constitution and biochemical activity of chromatin remodeling complexes has been extensively studied in yeast and using in vitro cell culture systems, but large gaps in our knowledge still remain concerning the precise roles for these proteins in vivo. This proposal is aimed at understanding the in vivo role of one such protein, ATRX, using the mouse as a model system. ATRX was classified as a member of the SWI/SNF family of chromatin remodeling proteins based on homology within the ATPase/helicase domain. The clinical phenotypes of patients with Atrx mutations suggest that it regulates genes controlling a diverse array of developmental pathways. Prominent defects include alpha thalassemia and profound mental retardation, which are key indicators for the ATRX (X-linked alpha- thalassemia and mental retardation) syndrome. Other developmental abnormalities include gonadal dysgenesis, skeletal defects, and variable effects on the gastrointestinal, cardiac, and renal systems. Despite the large number of potential targets for Atrx, the alpha globin gene is the only known target, and even for this locus, the etiology of the defect is not understood. This proposal proposes experiments that will provide basic knowledge about the in vivo roles of Atrx.
