Renln-expresslng cells are crucial in the control of blood pressure, fluid and electrolyte homeostasis and development ofthe kidney vasculature. Understanding the molecular mechanisms governing the acquisition of renin cell identity-and their plasticity to switch the renin phenotype on and off- is of fundamental biological and medical relevance. With the support of the R37 we generated mouse and cell models which allowed us to demonstrate that the identity and plasticity ofthe renin cell is determined by chromatin remodeling at the renin gene resulting from the balance between histone methylation and acetylation marks at the renin promoter. We further showed that cAMP plays a central role in the regulation of renin expression and renin cell identity and that the transcriptional effects of cAMP are mediated by the binding of CREB and histone acetyl transferases CBP/p300 to the cAMP response element (CRE) located in the enhancer region ofthe renin gene. While there is still work to be completed, the results obtained during the current cycle allow us to formulate with confidence a plan that will expand the depth of our understanding as to how renin cell identity is regulated. The overall hypothesis to be tested is that the identity of the renin cell is determined by the three- dimensional conformation of chromatin governed by: 1) renin gene locus specific and associated genome- wide epigenetic marks such as histone acetylation and methylation and DNA methylation patterns, 2) the establishment of gene-gene interactions and transcriptional factories ultimately responsible for the coordinated expression ofthe genes that confer the renin cell with its unique identity, and 3) interactions of the CRE (and associated Creb/CBP/p300) of the renin gene enhancer with regulatory elements within the renin gene (RBP-J, Hox/Pbx sites) and other genes in the genome are ultimately responsible for the pattern of unique genome-wide epigenetic changes, chromosomal looping and transcriptional factories that determine the identity and fate of the renin cell.
The proposed work should provide fundamental new information regarding the molecular-genomic mechanisms that control renin cell identity and plasticity. Novel information gained form these studies may be of benefit to individuals affected by hypertension, cardiovascular diseases involving tissue repair, vascular development and renal diseases resulting from abnormal vascular structure and/or differentiation.
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