Abstract P152: Chromatin Accessibility Landscape Of The Proximal Tubule And Thick Ascending Limb In Humans And Rats

Abstract

Hypertension is a major risk factor for disease burden and mortality. A decrease in the kidney’sability to excrete sodium can lead to hypertension. Specifically, the proximal tubule (PT) and thickascending limb (TAL) of the nephron play crucial roles in the reabsorption of filtered sodium toregulate blood pressure (BP). Understanding the genetic and epigenetic factors that influence PTand TAL functions is essential for unraveling the molecular mechanisms underlying hypertension.GWAS identified over 1,000 BP-associated genomic loci comprising > 26,000 SNPs. Most (~90%)are in intronic and intergenic regions and may influence BP-relevant gene expression by yetunexplored epigenetic mechanisms. Better understanding of how non-coding genomic regionsregulate BP is critical to defining the genetic underpinnings of hypertension. To address this, weestablished chromatin state (open and closed chromatin) maps for PT and TAL from humans andinbred salt-sensitive rats (SS/JrHsdMcwi) using the Assay for Transposase-Accessible Chromatinwith Sequencing (ATAC-Seq). Linear dimensional reduction revealed that in both species, PT andTAL segments clearly separated, indicating their chromatin states were distinct. ATAC-seq “peaks”represent regions of open chromatin, and therefore likely to be within regulatory elements. Ahigher number of differential peaks was identified between human PT and TAL (65,823) comparedto rat (1,063). The number of PT and TAL enriched peaks also differs between species. Genomicdistribution of these differential peaks indicates the bulk fall within distal intergenic and intronicregions (human: 71.64%, rat: 88.81%) rather than the gene promoters or exonic regions for bothspecies. This indicates that the chromatin accessibility of regulatory regions is significantlydifferent between these two segments for both species. Our next steps are to identify upstreamregulators that differ between the kidney segments and species and integrate ATAC-Seq data withexpression data to define the association of non-coding regions with transcript levels. Our workhas generated chromatin state maps that may improve the understanding of the role of noncodinggenomic regions in the transcriptional regulation in PT and TAL in human and rat.