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Epigenetic Regulation of Arginine Vasopressin Receptor 2 expression by PAX2 and Pax Transcription Interacting Protein.

The renal arginine vasopressin receptor 2 (AVPR2) plays a crucial role in osmoregulation. Engagement of ligand with the AVPR2 results in aquaporin 2 movement to the apical membrane and water reabsorption from the urinary filtrate. Despite an essential role, little is known about transcriptional regulation of the Avpr2. Here we identify novel roles for PAX2, a transcription factor crucial for kidney development, and its adaptor protein PTIP for epigenetic regulation of the Avpr2 and thus body water balance. Chromatin immunoprecipitation (ChIP) from murine inner medulla cells (IMCD-3) identified the minimal DNA-binding region of PAX2 on the Avpr2 promoter. Regulation of the Avpr2 by PAX2 was confirmed using a heterologous DNA expression system. PAX2 recruits the adaptor protein PTIP and its associated Histone Methyl Transferase (HMT) complex to the Avpr2 promoter imposing epigenetic marks on this region and throughout the coding sequence that modulate Avpr2 gene transcription. Reduction of PAX2 or PTIP protein levels by short-interfering RNA prevented histone lysine methylation and expression of Avpr2. ChIP using mouse or human kidney determined that PAX2 is highly enriched in the AVPR2 promoter alongside PTIP and HMT proteins, leading to high levels of histone H3 lysine trimethylation within the promoter and throughout the gene. In conclusion, PAX2 provides locus specificity for PTIP allowing the HMT complex to impart epigenetic changes at the Avpr2 locus and regulate Avpr2 transcription. These finding have major implications for understanding regulation of body water balance.