Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

Mouri, Kousuke; Guo, Michael H.; Boer, Carl G. de; Lissner, Michelle M; Harten, Ingrid A.; Newby, Gregory A.; DeBerg, Hannah A.; Platt, Winona F; Gentili, Matteo; Liu, David R.; Campbell, Daniel; Hacohen, Nir; Tewhey, Ryan; Ray, John J.

doi:10.1038/s41588-022-01056-5

Cited by 41 publications

(23 citation statements)

References 74 publications

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“…This enhancer was linked to BACH2 , which was also the closest gene to this fine-mapped variant. Notably, base-editing in T cells has confirmed that this variant affects BACH2 expression 80 . Moreover, editing of this variant into CD8 T cells skewed naive T cells toward effector T cell fates 80 .…”

Section: Resultsmentioning

confidence: 94%

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Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles

Sakaue

Weinand

Isaac

et al. 2022

Preprint

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Translating genome-wide association study (GWAS) loci into causal variants and genes requires accurate cell-type-specific enhancer-gene maps from disease-relevant tissues. Building enhancer-gene maps is essential but challenging with current experimental methods in primary human tissues. We developed a new non-parametric statistical method, SCENT (Single-Cell ENhancer Target gene mapping) which models association between enhancer chromatin accessibility and gene expression in single-cell multimodal RNA-seq and ATAC-seq data. We applied SCENT to 9 multimodal datasets including > 120,000 single cells and created 23 cell-type-specific enhancer-gene maps. These maps were highly enriched for causal variants in eQTLs and GWAS for 1,143 diseases and traits. We identified likely causal genes for both common and rare diseases. In addition, we were able to link somatic mutation hotspots to target genes. We demonstrate that application of SCENT to multimodal data from disease-relevant human tissue enables the scalable construction of accurate cell-type-specific enhancer-gene maps, essential for defining variant function.

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Section: Resultsmentioning

confidence: 94%

“…Moreover, editing of this variant into CD8 T cells skewed naive T cells toward effector T cell fates 80 . Figure 4.…”

Section: Defining Mechanisms Of Gwas Loci By Scentmentioning

confidence: 99%

Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles

Sakaue

Weinand

Isaac

et al. 2022

Preprint

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“…2a ). NCVs that had statistically significant allelic skew between the reference and alternate alleles were called expression-modulating variants (emVars) 41 ( Supplementary Table 2) . Since only a subset of DNA regions are active (show MPRA activity for either allele), we calculated the validation rate as the ratio of emVars over the total number of active DNA regions for each NCV category.…”

Section: Resultsmentioning

confidence: 99%

Widespread perturbation of ETS factor binding sites in cancer

Pro

Hook

Bray

et al. 2022

Preprint

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Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

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“…Let us not end with emphasizing this daunting task ahead; allow us to point to a recent inspiring study in which a high-throughput approach worked well to graze a landscape with hundreds of autoimmune disease-associated loci and enabled the definition of five dozen putatively causal variants, subsequently one of these SNPs was introduced in mice and human cells to allow disclosure of its physiologically relevant effect ( Mouri et al, 2022 ). Thus, although thousands of verdicts are still out, in the end we will be able to prove hereditable variants of classical PTP genes either innocent or guilty.…”

Section: Discussionmentioning

confidence: 99%

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

Hendriks

Cruchten

Pulido

2023

Front. Cell Dev. Biol.

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Protein tyrosine phosphatases, together with protein tyrosine kinases, control many molecular signaling steps that control life at cellular and organismal levels. Impairing alterations in the genes encoding the involved proteins is expected to profoundly affect the quality of life—if compatible with life at all. Here, we review the current knowledge on the effects of germline variants that have been reported for genes encoding a subset of the protein tyrosine phosphatase superfamily; that of the thirty seven classical members. The conclusion must be that the newest genome research tools produced an avalanche of data that suggest ‘guilt by association’ for individual genes to specific disorders. Future research should face the challenge to investigate these accusations thoroughly and convincingly, to reach a mature genotype-phenotype map for this intriguing protein family.

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Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells

Cited by 41 publications

References 74 publications

Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles

Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles

Widespread perturbation of ETS factor binding sites in cancer

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

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