Novel long-range regulatory mechanisms controlling PKD2 gene expression

Stéphanie Moisan,Marie-Pierre Audrézet,Yannick Le Meur,Josée Dostie,Emilie Cornec-Le Gall,Claude Férec,Stéphanie Levon

doi:10.1186/s12864-018-4892-6

Abstract

BackgroundCis-regulatory elements control gene expression over large distances through the formation of chromatin loops, which allow contact between enhancers and gene promoters. Alterations in cis-acting regulatory systems could be linked to human genetic diseases. Here, we analyse the spatial organization of a large region spanning the polycystic kidney disease 2 (PKD2) gene, one of the genes responsible of autosomal dominant polycystic kidney disease (ADPKD).ResultsBy using chromosome conformation capture carbon copy (5C) technology in primary human renal cyst epithelial cells, we identify novel contacts of the PKD2 promoter with chromatin regions, which display characteristics of regulatory elements. In parallel, by using functional analysis with a reporter assay, we demonstrate that three DNAse I hypersensitive sites regions are involved in the regulation of PKD2 gene expression.ConclusionsFinally, through alignment of CCCTC-binding factor (CTCF) sites, we suggest that these novel enhancer elements are brought to the PKD2 promoter by chromatin looping via the recruitment of CTCF.

Highlights

Cis-regulatory elements control gene expression over large distances through the formation of chromatin loops, which allow contact between enhancers and gene promoters
Through alignment of CCCTC-binding factor (CTCF) sites, we suggest that these novel enhancer elements are brought to the polycystic kidney disease 2 (PKD2) promoter by chromatin looping via CTCF
Analysing the human PKD2 locus with the Chromosome conformation capture carbon copy (5C) technology Very little is known about the regulatory elements that control PKD2 transcription

Summary

Introduction

Cis-regulatory elements control gene expression over large distances through the formation of chromatin loops, which allow contact between enhancers and gene promoters. We analyse the spatial organization of a large region spanning the polycystic kidney disease 2 (PKD2) gene, one of the genes responsible of autosomal dominant polycystic kidney disease (ADPKD). Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian genetic disorders with an incidence of 1/400 to 1/2000 affected individuals worldwide [1]. The disorder is heterogeneous with two main genes, polycystic kidney disease 1 (PKD1) and 2 (PKD2), which are responsible for most disease cases [2, 3]. A third gene, GANAB has recently been identified as accounting for less than 1% of affected patients [4]. There is significant clinical heterogeneity in the severity of the disease among patients as well as within the same family

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