A systems biology approach to identify cortical and medullary gene regulatory networks related to Hypoxia Inducible Factor-1A

ABSTRACT Acute Kidney Injury (AKI) is a common and costly complication in hospitalized patients, which is associated with high mortality. Many episodes of AKI are due to episodes of hypoxia, and cells in the kidney medulla are particularly susceptible to hypoxic injury. Hypoxia Inducible Factor-1A (HIF1A) is a key transcription factor regulating the response to hypoxia. While HIF1A has been well characterized, it is still poorly understood how the target genes of HIF1A are regulated in a physiologically low oxygen environment, such as the kidney medulla. Preliminary data from percutaneous kidney biopsies sampling mainly the kidney cortex of individuals show that HIF1A target genes exhibit cell type enrichment. Transcription factor cooperativity may explain cell type enrichment and in silico promoter analysis predicted transcription factors that co-modulate with HIF1A in the promoter region. To expand upon these findings, this project proposes to use multiome data from the Kidney Precision Medicine Project to validate that the predicted transcription factor motifs are located in areas of open chromatin (Aim 1A). We will additionally generate multiome data from kidney samples that are sectioned into cortical and medullary regions. This project then aims to identify the gene regulatory network for the kidney cortex and medulla with respect to HIF1A (Aim 1B). As adaptive cell states are associated with poor long-term outcomes, we will then identify aspects of the gene regulatory network that are perturbed in adaptive cell states by identifying nodes of the network with differentially accessible chromatin between healthy and adaptive cell states (Aim 2). These data will provide important insight into how HIF1A target genes are differentially regulated in kidney cortex and medulla and identify epigenetic alterations that may contribute to maladaptive repair after an episode of Acute Kidney Injury.