Multi-omic Analysis of Primary Human Kidney Tissues Identifies Medulla-Specific Gene Expression Patterns

Abstract

The renal medulla is a specialized region of the kidney with important homeostatic functions. It has also been implicated in genetic and developmental disorders and ischemic and drug-induced injuries. Despite its role in kidney function and disease, the medulla's baseline gene expression and epigenomic signatures have not been well described in the adult human kidney. Here we generate and analyze gene expression (RNA-seq), chromatin accessibility (ATAC-seq) and chromatin conformation (Hi-C) data from adult human kidney cortex and medulla. Using data from our carefully annotated specimens, we assign samples in the larger public GTEx database to cortex and medulla, thereby identifying several misassignments and extracting meaningful medullary gene expression signatures. Using integrated analysis of gene expression, chromatin accessibility and conformation profiles, we reveal insights into medulla development and function. Our datasets will also provide a valuable resource for researchers in the GWAS community for functional annotation of genetic variants.

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

“…The factors that control these changes are not fully understood. There is plenty of evidence that the unique hypertonic environment in the renal inner medulla mediates a specific gene expression pattern 12, 29, 52 31 . With this study, we provide evidences that the differences in the chromatin accessibility contribute to the observed changes.…”

“…This data indicates that the enriched Aqp2 expression in the IM is associated with increased accessibility at the TSS and that probably hypertonicity induces the observed differences. Recently, Haug et al analysed chromatin accessibility and spatial transcription in the adult human kidney cortex and medulla 31 . Haug et al identified around 2,300 differentially expressed genes between renal cortex and renal medulla.…”

“…Recently, Haug et al published a study on human kidney samples, using gene expression profiling and epigenetic changes to characterize spatial differences in gene expression between the renal cortex and inner medulla 31 . As described above one factor that influences spatial gene expression is the corticomedullary osmotic gradient and the action of NFAT5.…”

Challenges and Opportunities for the Clinical Translation of Spatial Transcriptomics Technologies

“…These investigators examined both glomerular and tubulointerstitial ROIs and found that antibody-mediated rejection was more pronounced in glomeruli with influx of monocytes, macrophages, and natural killer cells. Finally, we have recently shown that spatial profiling can be used to validate findings from other -omics technologies in place of traditional techniques such as immunohistochemistry [ 55 ].…”