Epigenetic Regulation of Hormonal Response

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In order to study the epigenetic components of enhanced retinoid responsiveness we performed an in depth epigenetic characterization of the events taking place on the promoter of a retinoid regulated gene, tissue transglutaminase type 2. As a result of our studies, we propose a new model for the epigenetic regulation of retinoid response and differentiation competence in myeloid leukemia cells. We found that H4R3 methylation, a modification identified previously but withouta well defined biological role, is a hallmark of the primed cell state and precedes gene activation. This modification represents a transcriptional silent (unproductive), but primed state that marks key histones and makes them better substrates for receptor bound acetyltransferases (HAT-s). We propose that this mechanism accounts for the increased susceptibility of the cell to respond to a terminal differentiating agents, such as a retinoid, with increased gene expression and an increased potential for phenotypic differentiation. This model is consistent with the proposal that histone tail modifications function as the physical mediators of cellular memory. By providing docking sites for transcription factors and marking histones for subsequent covalent modifications, these methylation reactions serve as silent switches of gene expression. Our findings suggest an active and physiological role for arginine 3 methylation on H4 tails in retinoid response and provide a model amenable to further investigation and potentially to pharmacological exploitation. In order to further characterize the role of arginine methylation in signal integration and developmental processes we carried out mapping of the genomic loci marked by PRMT1 via histone H4 arginine 3 methylation. We used chromatin immunoprecipitation and cloning to isolate genomic loci marked by H4R3 methylation. After sequencing and in silico analysis we found that all of the genomic hits identified were intronic or at 5‘ end of specific genes. The locations identified were enriched in conserved transcription factor binding sites of POU2F1, MEF-2 and FOXL1 factors. A great number of the genes in the proximity of the identified genomic loci were involving signaling pathways and developmental processes.