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Promoter-Interacting Expression Quantitative Trait Loci (pieQTLs) in Human Immune Cell Types

56 Pages Posted: 10 Jun 2019 Publication Status: Review Complete

See all articles by Vivek Chandra

Vivek Chandra

La Jolla Institute for Immunology

Sourya Bhattacharyya

La Jolla Institute for Immunology

Benjamin J. Schmiedel

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Ariel Madrigal

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Stephanie Fotsing

La Jolla Institute for Immunology

Gregory Seumois

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Mitchell Kronenberg

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

Bjoern Peters

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

Ferhat Ay

La Jolla Institute for Allergy and Immunology (LIAI); University of California, San Diego (UCSD) - School of Medicine

Pandurangan Vijayanand

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

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Abstract

Expression quantitative trait loci (eQTLs) studies provide associations of genetic variants with gene expression but fall short of pinpointing functionally important eQTLs or providing mechanistic insights. Using proximity ligation-assisted H3K27ac ChIP-seq (HiChIP/PLAC-seq) assays, here we mapped eQTLs that overlap active cis-regulatory elements and interact with their target gene promoters (promoter-interacting eQTLs, pieQTLs) in five common immune cell types. This allowed us to narrow down functionally important eQTLs to a small minority and show mechanisms that explain their cell type restriction. We demonstrated genotype-dependent correlation between frequency of pieQTL interactions and gene expression. In addition, we discovered ultralong distance pieQTLs including several disease-risk variants, and new eGenes such as FHIT for which we validated the functional role of an eQTL-overlapping cis-regulatory element located >1Mb away from its promoter by CRISPRi assays. Our study provides insights into cell-specific gene regulation and highlights the potentially functional non-coding variants (pieQTLs) linked to human diseases.

Keywords: GWAS, eQTL, DICE, Immune cells, Chromosome conformation capture, HiChIP

Suggested Citation

Chandra, Vivek and Bhattacharyya, Sourya and Schmiedel, Benjamin J. and Madrigal, Ariel and Fotsing, Stephanie and Seumois, Gregory and Kronenberg, Mitchell and Peters, Bjoern and Ay, Ferhat and Vijayanand, Pandurangan, Promoter-Interacting Expression Quantitative Trait Loci (pieQTLs) in Human Immune Cell Types (June 10, 2019). Available at SSRN: https://ssrn.com/abstract=3402070 or http://dx.doi.org/10.2139/ssrn.3402070
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Vivek Chandra

La Jolla Institute for Immunology ( email )

La Jolla, CA
United States

Sourya Bhattacharyya

La Jolla Institute for Immunology

La Jolla, CA
United States

Benjamin J. Schmiedel

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

9420 Athena Cir
La Jolla, CA 92037
United States

Ariel Madrigal

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

La Jolla, CA 92037
United States

Stephanie Fotsing

La Jolla Institute for Immunology

La Jolla, CA
United States

Gregory Seumois

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

La Jolla, CA 92037
United States

Mitchell Kronenberg

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Developmental Immunology

9420 Athena Cir
La Jolla, CA 92137
United States

Bjoern Peters

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

9420 Athena Cir
La Jolla, CA 92037
United States

Ferhat Ay

La Jolla Institute for Allergy and Immunology (LIAI)

9420 Athena Cir
La Jolla, CA 92037
United States

University of California, San Diego (UCSD) - School of Medicine

9500 Gilman Drive
MC 0507
La Jolla, CA 92093
United States

Pandurangan Vijayanand (Contact Author)

La Jolla Institute for Allergy and Immunology (LIAI) - Division of Vaccine Discovery

La Jolla, CA 92037
United States

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