Differences in chromatin accessibility between renal cortex and inner medulla correlate with spatial differences in gene expression and are modulated by NFAT5 function

Abstract

A spatial gene expression pattern between the cortex (CTX) and inner medulla (IM) of the kidney has been observed, but the underlying mechanisms are unclear. Understanding these mechanisms is essential for elucidating renal function. Using the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) we analyzed the open chromatin structures and the involvement of epigenetic mechanisms in mediating gene expression differences between the renal CTX and 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 work demonstrates for the first time that these differences in gene expression between renal CTX and IM are associated with an epigenetic mechanism driven by chromatin accessibility, which is partially modulated by the nuclear factor of activated T-cells 5 (NFAT5) in mice. Furthermore, spatial localization and NFAT5-promoted chromatin accessibility correlate with differential gene expression and altered promoter binding motif enrichment in CTX and IM. This study provides new insights into the spatial and NFAT5-mediated regulation of chromatin accessibility and gene expression in CTX and IM. This work advances our understanding of kidney physiology by uncovering previously unknown epigenetic factors influencing gene expression and provides a new perspective on renal adaptive mechanisms. TRANSLATIONAL STATEMENTThe study reveals new insights into the spatial and epigenetic regulation of gene expression in the renal cortex (CTX) and inner medulla (IM) in the mouse kidney. We used the Assay for Transposase-Accessible Chromatin with High-Throughput Sequence Analysis (ATAC-seq) to identify a key role of NFAT5 in modulating chromatin accessibility and to uncover previously unknown epigenetic factors. This research enhances our understanding of renal physiology and has important implications for clinical care by providing insights into potential adaptive mechanisms in the kidney. These findings suggest future investigations targeting epigenetic signaling pathways for therapeutic intervention in renal diseases.