Effect of hypertonicity on chromatin accessibility and contribution of NFAT5

Understanding the mechanisms underlying cell type-specific gene expression in the kidney is essential to elucidate renal function. Using the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) we analyzed open chromatin structures and the involvement of epigenetic mechanisms in mediating gene expression differences between the renal cortex (CTX) and inner medulla (IM). We also examined the role of the nuclear factor of activated T cells 5 (NFAT5), a key regulator of hypertonicity. ATAC-seq analysis was performed on CTX and IM samples from both wild-type (WT) and NFAT5 knockout (KO) mice. This study revealed global differences in chromatin accessibility between renal CTX and IM and the impact of NFAT5 loss on open chromatin regions. Furthermore, spatial localization and NFAT5-promoted chromatin accessibility correlate with differential gene expression and altered promoter binding motif enrichment in CTX and IM. Our findings provide new insights into spatial and NFAT5-promoted transcriptional regulation in the kidney, and their importance for renal function and adaptation to osmotic stress. Overall design: Renal cortex and renal inner medulla from WT (Aqp2-Cre+/-) and NFAT5-KO (NFAT5fl/fl-AQP2-470 CRE+/-) mice were used for ATAC-seq analysis. Mice are deficient in NFAT5 in the principal cells (PC) of the collecting duct. 3 replicate samples per tissue were analyzed.