Paper

Genome-wide discovery of SLE genetic risk variant allelic enhancer activity

De Boer, Carl G, Parameswaran, Sreeja, Ray, John P, Donmez, Omer, Weirauch, Matthew T, Lu, Xiaoming, Cazares, Tareian, ney, Carmy, Huang, Yongbo, Hong, Ted, Chen, Xiaoting, Kottyan, Leah C, Harley, John B, Miraldi, Emily R, Pujato, Mario, Miller, Daniel

2021

Overview

Abstract Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into the Epstein-Barr virus-transformed B cell line GM12878 revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. Comparison of MPRA results in GM12878 and Jurkat T cell lines highlights shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around allelic variants identifies one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that bind allelically without direct alteration of their motif by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Deoxyribonucleic acid / DNA / Epstein-Barr virus / Gene regulation / Genetic diversity / Genome-wide association studies / Genomes / Genomics / Genotypes / Lupus / Lymphocytes B / Oligonucleotides / Systemic lupus erythematosus / Transfection