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

BMC Biology

Zhaohui Qin¹  Jing Zhang²  Qi Wang²  Hong Wang²  Yuexian Xing³  Qing Hou³  Zhaohong Chen³  Yan Zhu³  Jinhua Hou³  Zhihong Liu³  Jinsong Shi³  Aiping Duan³  Jingping Yang³ 

[1] Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, 1518 Clifton Road N.E, 30322, Atlanta, GA, USA;Medical School of Nanjing University, 210093, Nanjing, Jiangsu, China;National Clinical Research Center for Kidney Disease, Jinling Hospital, Medical School of Nanjing University, 210002, Nanjing, Jiangsu, China;Medical School of Nanjing University, 210093, Nanjing, Jiangsu, China;

关键词: Chromatin organization;    Epigenetic landscape;    Regulatory element;    Disease-associated variant;   

DOI  :  10.1186/s12915-021-00977-7

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY