Epromoters are new players in the regulatory landscape with potential pleiotropic roles

Malfait, Juliette; Wan, Jing; Spicuglia, Salvatore

doi:10.1002/bies.202300012

Cited by 4 publications

(2 citation statements)

References 101 publications

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“…Moreover, ESpromoters may have pleiotropic impacts on various physiological and pathological traits, by differentially regulating multiple proximal and distal genes at a given locus 18 . These genes may not necessarily be part of the same biological pathway but could be involved in pathogenic processes shared across different diseases.…”

Section: Discussionmentioning

confidence: 99%

“…These enhancers can activate gene transcription over large distances and independently of orientation. Recent studies have unveiled that a subset of promoters can also serve as enhancers, termed "Epromoters" [15][16][17][18] . Investigating these promoters, enhancers or Epromoters is essential for understanding complex gene regulation, as they wield the power to directly influence physiological traits or diseases by simultaneously regulating the expression of numerous proximal and distal genes.…”

Section: Introductionmentioning

confidence: 99%

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Unraveling a novel dual-function regulatory element showing epistatic interaction with a variant that escapes genome-wide association studies

Adjemout,

Nisar,

Escandell

et al. 2024

Preprint

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Regulation of gene expression has recently been complexified by the identification of Epromoters, a subset of promoters with enhancer function. Here, we uncovered the first dual cis-regulatory element, "ESpromoter," exhibiting both enhancer and silencer function, as a regulator of the nearby genes ATP2B4 and LAX1 in single human T cells. Through integrative approach, we pinpointed functional rs11240391, a severe malaria risk variant that escapes detection in genome-wide association studies, challenging conventional strategies for identifying causal variants. CRISPR-modified cells demonstrated the regulatory effect of ESpromoter and rs11240391 on LAX1 expression and T cell activation. Furthermore, our findings revealed an epistatic interaction between ESpromoter SNPs and rs11240391, impacting severe malaria susceptibility by further reducing LAX1 expression. This groundbreaking discovery challenges the conventional enhancer-silencer dichotomy. It highlights the sophistication of transcriptional regulation and argues for an integrated approach combining genetics, epigenetics, and genomics to identify new therapeutic targets for complex diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unraveling a novel dual-function regulatory element showing epistatic interaction with a variant that escapes genome-wide association studies

Adjemout,

Nisar,

Escandell

et al. 2024

Preprint

Self Cite

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Comprehensive mapping of genetic variation at Epromoters reveals pleiotropic association with multiple disease traits

Wan,

van Ouwerkerk,

Mouren

et al. 2024

Nucleic Acids Research

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There is growing evidence that a wide range of human diseases and physiological traits are influenced by genetic variation of cis-regulatory elements. We and others have shown that a subset of promoter elements, termed Epromoters, also function as enhancer regulators of distal genes. This opens a paradigm in the study of regulatory variants, as single nucleotide polymorphisms (SNPs) within Epromoters might influence the expression of several (distal) genes at the same time, which could disentangle the identification of disease-associated genes. Here, we built a comprehensive resource of human Epromoters using newly generated and publicly available high-throughput reporter assays. We showed that Epromoters display intrinsic and epigenetic features that distinguish them from typical promoters. By integrating Genome-Wide Association Studies (GWAS), expression Quantitative Trait Loci (eQTLs) and 3D chromatin interactions, we found that regulatory variants at Epromoters are concurrently associated with more disease and physiological traits, as compared with typical promoters. To dissect the regulatory impact of Epromoter variants, we evaluated their impact on regulatory activity by analyzing allelic-specific high-throughput reporter assays and provided reliable examples of pleiotropic Epromoters. In summary, our study represents a comprehensive resource of regulatory variants supporting the pleiotropic role of Epromoters.

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Integrated functional genomic analysis identifies the regulatory variants underlying a major QTL for disease resistance in European sea bass

Mukiibi,

Ferraresso,

Franch

et al. 2024

Preprint

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BackgroundViral nervous necrosis (VNN) is a viral disease threatening the sustainability of global aquaculture, and affecting over 50 of farmed and ecologically important species. A major QTL for resistance to VNN has been previously described in European sea bass, but the underlying causal gene(s) and mutation(s) are unknown. To identify the mechanisms and genetic factors underpinning resistance to VNN, we integrated farmed and wild genetic data with multiple functional genomics assays in a farmed European sea bass population.ResultsA high heritability (h2 ∼ 0.40) was estimated for VNN resistance. A major QTL for this trait was confirmed on chromosome 3, and whole-genome resequencing narrowed its location to a small region containing 4 copies of interferon alpha inducible protein 27-like 2A (IFI27L2A) genes, and one copy of the interferon alpha inducible protein 27-like 2 (IFI27L2) gene. RNA sequencing revealed a clear association between the QTL genotype and the expression of two of theIFI27L2Agenes, and theIFI27L2gene. Integration with chromatin accessibility and histone modification data pinpointed two SNPs in active regulatory regions of two of these genes (IFI27L2AandIFI27L2), and transcription factor binding site gains for the resistant alleles were predicted. These alleles, particularly the SNP variant CHR3:10077301, exhibited higher frequency in Eastern Mediterranean sea bass populations, which show considerably higher levels of resistance to VNN.ConclusionsThe SNP variant CHR3:10077301, through modulation ofIFI27L2andIFI27L2Agenes, is likely the causative mutation underlying resistance to VNN in European sea bass. This is one of the first causative mutations discovered for disease resistance traits, and paves the way for marker-assisted selection as well as biotechnological approaches to enhance resistance to VNN in European sea bass and other susceptible species.

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Epromoters are new players in the regulatory landscape with potential pleiotropic roles

Cited by 4 publications

References 101 publications

Unraveling a novel dual-function regulatory element showing epistatic interaction with a variant that escapes genome-wide association studies

Unraveling a novel dual-function regulatory element showing epistatic interaction with a variant that escapes genome-wide association studies

Comprehensive mapping of genetic variation at Epromoters reveals pleiotropic association with multiple disease traits

Integrated functional genomic analysis identifies the regulatory variants underlying a major QTL for disease resistance in European sea bass

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