|
| Status |
Public on Jan 31, 2021 |
| Title |
Global discovery of SLE genetic risk variant allelic enhancer activity |
| Organisms |
Homo sapiens; unidentified plasmid |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
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 assays (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into 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. Combined with allelic enhancer activity analyses in Jurkat cell line, we identified shared and unique allelic transcriptional regulatory mechanisms at SLE risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around 51 allelic variants identified 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 also bind allelically but do not have their motifs directly altered 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.
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| |
|
| Overall design |
Massively parallel reporter assays to study SLE associated variants for risk allele-dependent transcriptional enhancer activity, 3-5 replicates, 2 conditions, 2 cell types
|
| |
|
| Contributor(s) |
Lu X, Chen X |
| Citation(s) |
33712590 |
| |
| Submission date |
Jan 16, 2020 |
| Last update date |
Apr 07, 2021 |
| Contact name |
Xiaoming Lu |
| Organization name |
Cincinnati Children's Hospital Medical Center
|
| Department |
Center for Autoimmune Genomics and Etiology (CAGE)
|
| Lab |
Leah Kottyan
|
| Street address |
3333 Burnet Ave
|
| City |
Cincinnati |
| State/province |
Ohio |
| ZIP/Postal code |
45229 |
| Country |
USA |
| |
|
| Platforms (3) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
| GPL28010 |
Illumina NextSeq 500 (unidentified plasmid) |
|
| Samples (25)
|
|
| Relations |
| BioProject |
PRJNA601725 |
| SRA |
SRP242208 |
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