Chromatin State Maps of Blood Pressure-Relevant Renal Segments Reveal Potential Regulatory Role for SNPs

Hypertension or elevated blood pressure (BP) is a worldwide clinical challenge and the leading primary risk factor for kidney dysfunctions, heart failure, and cerebrovascular disease. The kidney is a central regulator of BP by maintaining sodium-water balance. Multiple genome-wide association studies revealed that BP is a heritable quantitative trait, modulated by several genetic, epigenetic, and environmental factors. The SNPs identified in genome-wide association studies predominantly (>95%) reside within noncoding genomic regions, making it difficult to understand how they regulate BP. Given the central role of the kidney in regulating BP, we hypothesized that chromatin-accessible regions in renal tissue would be enriched for BP-associated single nucleotide polymorphisms.

We manually dissected 2 important kidney segments that maintain the sodium-water balance: proximal tubules and medullary thick ascending limbs from the human and rat kidneys. To delineate their chromatin and transcriptomic profiles, we performed the assay for transposase-accessible chromatin and RNA sequencing, respectively.

The chromatin accessibility maps revealed the shared and unique cis-regulatory elements that modulate the chromatin accessibility in proximal tubule and medullary thick ascending limbs of humans and rats. We developed a visualization tool to compare the cross-species epigenomic maps to identify potential regulatory targets for hypertension pathogenesis. We also identified a significant enrichment of BP-associated single nucleotide polymorphisms (1064 for human proximal tubule and 1172 for human medullary thick ascending limbs) within accessible chromatin regions of both segments, including rs1173771 and rs1421811 at the NPR3 locus and rs1800470 at the TGFb1 locus.

Collectively, this study lays a foundation for interrogating how intergenic single nucleotide polymorphisms may regulate polygenic traits such as BP.