Chromatin architecture reveals cell type-specific target genes for kidney disease risk variants

Aiping Duan,Jingping Yang,Zhaohong Chen,Yuexian Xing,Jing Zhang,Zhaohui Qin,Hong Wang,Qi Wang,Jinhua Hou,Yan Zhu,Jinsong Shi,Zhihong Liu,Qing Hou

doi:10.1186/s12915-021-00977-7

Abstract

BackgroundCell type-specific transcriptional programming results from the combinatorial interplay between the repertoire of active regulatory elements. Disease-associated variants disrupt such programming, leading to altered expression of downstream regulated genes and the onset of pathological states. However, due to the non-linear regulatory properties of non-coding elements such as enhancers, which can activate transcription at long distances and in a non-directional way, the identification of causal variants and their target genes remains challenging. Here, we provide a multi-omics analysis to identify regulatory elements associated with functional kidney disease variants, and downstream regulated genes.ResultsIn order to understand the genetic risk of kidney diseases, we generated a comprehensive dataset of the chromatin landscape of human kidney tubule cells, including transcription-centered 3D chromatin organization, histone modifications distribution and transcriptome with HiChIP, ChIP-seq and RNA-seq. We identified genome-wide functional elements and thousands of interactions between the distal elements and target genes. The results revealed that risk variants for renal tumor and chronic kidney disease were enriched in kidney tubule cells. We further pinpointed the target genes for the variants and validated two target genes by CRISPR/Cas9 genome editing techniques in zebrafish, demonstrating that SLC34A1 and MTX1 were indispensable genes to maintain kidney function.ConclusionsOur results provide a valuable multi-omics resource on the chromatin landscape of human kidney tubule cells and establish a bioinformatic pipeline in dissecting functions of kidney disease-associated variants based on cell type-specific epigenome.

Highlights

Cell type-specific transcriptional programming results from the combinatorial interplay between the repertoire of active regulatory elements
Over the past decade, genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with a wide variety of human diseases, including kidney diseases [1, 2]
Our analyses discovered enrichment of causal variants for renal cell carcinoma (RCC) and chronic kidney disease (CKD) in kidney tubular cells

Summary

Introduction

Cell type-specific transcriptional programming results from the combinatorial interplay between the repertoire of active regulatory elements. Due to the non-linear regulatory properties of non-coding elements such as enhancers, which can activate transcription at long distances and in a non-directional way, the identification of causal variants and their target genes remains challenging. We provide a multi-omics analysis to identify regulatory elements associated with functional kidney disease variants, and downstream regulated genes. Compared to causal variant identification, searching for the target genes of these variants is even more challenging. Regulatory elements such as enhancers can regulate their target genes regardless of distance and direction [12]; it is unreliable to predict their target genes by genomic proximity alone. We believe that epigenomic features can help distinguish the causal variants from the others and facilitate the identification of the target genes for regulatory variants

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Results

Discussion

Conclusion