During this reporting period the Laboratory of Genetics and Physiology has continued and expanded a program aimed at exploring the role of cytokine-STAT5 signaling in epigenetic programming of cells. We have isolated mouse embryonic fibroblasts that contain or are devoid of STAT5 and established the genome-wide binding profile of the transcription factor STAT5A in the absence and presence of growth hormone. We have established for the first time that STAT5A also binds to specific DNA sequences in the absence of growth hormone. Furthermore we have identified more than 7000 genetic loci that are recognized specifically by STAT5A upon growth hormone stimulation. It is well established that the chromatin status at genetic loci determines their activity. To investigate the role of STAT transcription factors in modulating chromatin, we are in the process of analyzing on a genome-wide level chromatin modifications in the absence and presence of STAT5 and in the absence and presence of cytokine stimulation. Towards this goal we have isolated mouse embryonic fibroblasts that either carry Stat5 genes or lack them. Preliminary studies suggest that STAT5 transcription factor binding upon cytokine stimulation is accompanied by chromatin modeling that poises genes and genetic programs for activation. Studies to link cytokine-induced STAT5 binding with chromatin modeling are ongoing.
