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Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.

ABSTRACT: The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

SUBMITTER: Kang JB

PROVIDER: S-EPMC10055604 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.

Kang Joyce B JB Shen Amber Z AZ Sakaue Saori S Luo Yang Y Gurajala Saisriram S Nathan Aparna A Rumker Laurie L Aguiar Vitor R C VRC Valencia Cristian C Lagattuta Kaitlyn K Zhang Fan F Jonsson Anna Helena AH Yazar Seyhan S Alquicira-Hernandez Jose J Khalili Hamed H Ananthakrishnan Ashwin N AN Jagadeesh Karthik K Dey Kushal K Daly Mark J MJ Xavier Ramnik J RJ Donlin Laura T LT Anolik Jennifer H JH Powell Joseph E JE Rao Deepak A DA Brenner Michael B MB Gutierrez-Arcelus Maria M Raychaudhuri Soumya S

medRxiv : the preprint server for health sciences 20230320

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissu ...[more]

PMID: 36993194

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Project description:Gene expression is coordinated by a multitude of transcription factors (TFs), whose binding to the genome is directed through multiple interconnected epigenetic signals, including chromatin accessibility and histone modifications. These complex networks have been shown to be disrupted during aging, disease, and cancer. However, profiling these networks across diverse cell types and states has been limited due to the technical constraints of existing methods for mapping DNA:Protein interactions in single cells. As a result, a critical gap remains in understanding where TFs or other chromatin remodelers bind to DNA and how these interactions are perturbed in pathological contexts. To address this challenge, we developed a transformative single-cell immuno-tethering DNA:Protein mapping technology. By coupling a species-specific antibody-binding nanobody to a cytosine base editing enzyme, this approach enables profiling of even weak or transient factor binding to DNA, a task that was previously unachievable in single cells. Thus, our Docking & Deamination followed by sequencing (D&D-seq) technique induces cytosine-to-uracil edits in genomic regions bound by the target protein, offering a novel means to capture DNA:Protein interactions with unprecedented resolution. Importantly, this technique can be seamlessly incorporated into common single-cell multiomics workflows, enabling multimodal analysis of gene regulation in single cells. We tested the ability of D&D-seq to record TF binding both in bulk and at the single-cell level by profiling CTCF and GATA family members, obtaining high specificity and efficiency, with clear identification of TF footprint and signal retention in the targeted cell subpopulations. Furthermore, the deamination reaction showed minimal off-target activity, with high concordance to bulk ChIP-seq reference data. Applied to primary human peripheral blood mononuclear cells (PBMCs), D&D-seq successfully identified CTCF binding sites and enabled integration with advanced machine-learning algorithms for predicting 3D chromatin structure. Furthermore, we integrated D&D-seq with single-cell genotyping to assess the impact of IDH2 mutations on CTCF binding in a human clonal hematopoiesis sample, uncovering altered binding and chromatin co-accessibility patterns in mutant cells. Altogether, D&D-seq represents an important technological advance enabling the direct mapping of TF or chromatin remodeler binding to the DNA in primary human samples, opening new avenues for understanding chromatin and transcriptional regulation in health and disease.

Dataset Information

Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.

Publications

Mapping the dynamic genetic regulatory architecture of <i>HLA</i> genes at single-cell resolution.

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