Genome-wide enhancer maps link risk variants to disease genes

Nasser, Joseph; Bergman, Drew T.; Fulco, Charles P.; Guckelberger, Philine; Doughty, Benjamin R.; Patwardhan, Tejal A.; Jones, Thouis R.; Nguyen, Tung H.; Ulirsch, Jacob C.; Lekschas, Fritz; Mualim, Kristy; Natri, Heini M.; Weeks, Elle M.; Munson, Glen; Kane, Michael F.; Kang, Helen Y.; Cui, Ang; Ray, John J.; Eisenhaure, Thomas; Collins, Ryan L.; Dey, Kushal Kumar; Pfister, Hanspeter; Price, Alkes L.; Epstein, Charles B.; Kundaje, Anshul; Xavier, Ramnik J.; Daly, Mark J.; Huang, Hailiang; Finucane, Hilary; Hacohen, Nir; Lander, Eric S.; Engreitz, Jesse M.

doi:10.1038/s41586-021-03446-x

Cited by 465 publications

(569 citation statements)

References 77 publications

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“…The ABC method for scoring enhancer elements and linking them to target genes was subsequently used. 23,24 Raw ATAC-seq and H3K27ac ChIP-seq reads from macular and retinal tissue were obtained from a publicly available dataset (GEO accession: GSE137311). 26 The data were then processed using a consistent pipeline.…”

Section: Analysis Of Variants Associated With Ncmdmentioning

confidence: 99%

“…Notably, our ability to detect and annotate enhancer elements is being transformed by emerging resources and tools such as the Encyclopedia of DNA Elements (ENCODE) 3 dataset, 20 the Developmental Single Cell Atlas of Gene Regulation and Expression (DESCARTES), 21,22 and the activity-by-contact (ABC) model. 23,24 The ENCODE project consortium and the DESCARTES team have generated extensive functional genomic datasets across many cell and tissue contexts. Experiments conducted include assays aiming to identify enhancer elements such as DNase-seq (DNase I hypersensitive site sequencing), H3K27ac ChIP-seq (chromatin immunoprecipitation sequencing mapping H3K27 acetylation signals), and ATAC-seq (assay for transposase-accessible chromatin using sequencing), as well as assays studying the 3-dimensional architecture of the genome such as Hi-C (all-versus-all chromosome conformation capture).…”

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confidence: 99%

“…This model is based on the notion that an enhancer's effect on a gene depends on the enhancer's strength (estimated using chromatin accessibility data including ATAC-seq and H3K27ac ChIP-seq data) weighted by how often it comes into three-dimensional contact with the gene promoter (estimated using Hi-C data). 23,24 Although this method has been shown to be accurate, a limiting factor is the availability of tissue-specific chromatin accessibility datasets. Comprehensive tissue-specific Hi-C data are also lacking, but the developers of ABC expect that Hi-C profiles averaged across a selection of cell types are adequate to map enhancer-gene connections.…”

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confidence: 99%

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North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants

Green

Lenassi

Manning

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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North Carolina macular dystrophy (NCMD) is an autosomal dominant, congenital disorder affecting the central retina. Here, we report clinical and genetic findings in three families segregating NCMD and use epigenomic datasets from human tissues to gain insights into the effect of NCMD-implicated variants. METHODS.Clinical assessment and genetic testing were performed. Publicly available transcriptomic and epigenomic datasets were analyzed and the activity-by-contact method for scoring enhancer elements and linking them to target genes was used. RESULTS.A previously described, heterozygous, noncoding variant upstream of the PRDM13 gene was detected in all six affected study participants (chr6:100,040,987G>C [GRCh37/hg19]). Interfamilial and intrafamilial variability were observed; the visual acuity ranged from 0.0 to 1.6 LogMAR and fundoscopic findings ranged from visually insignificant, confluent, drusen-like macular deposits to coloboma-like macular lesions. Variable degrees of peripheral retinal spots (which were easily detected on widefield retinal imaging) were observed in all study subjects. Notably, a 6-year-old patient developed choroidal neovascularization and required treatment with intravitreal bevacizumab injections. Computational analysis of the five single nucleotide variants that have been implicated in NCMD revealed that these noncoding changes lie within two putative enhancer elements; these elements are predicted to interact with PRDM13 in the developing human retina. PRDM13 was found to be expressed in the fetal retina, with greatest expression in the amacrine precursor cell population. CONCLUSIONS.We provide further evidence supporting the role of PRDM13 dysregulation in the pathogenesis of NCMD and highlight the usefulness of widefield retinal imaging in individuals suspected to have this condition.

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Section: Analysis Of Variants Associated With Ncmdmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants

Green

Lenassi

Manning

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…Investigating these focal chromatin interactions may provide insights on the relationship between CREs, such as between enhancers and their target gene promoter 66,67 , to better understand the etiology of disease.…”

Section: Discussionmentioning

confidence: 99%

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

Hawley

Zhou

Arlidge

et al. 2021

Preprint

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Prostate cancer is a heterogeneous disease whose progression is linked to genome instability 1. Despite large-scale tumour sequencing efforts, the impact of mutations on the genetic architecture in cancer remains ill-defined due to limited integration of genomics data across dimensions 2. We addressed this limitation by assessing the impact of structural variants on the chromatin states and the three-dimensional organization across benign and malignant primary prostate genomes. We find high concordance in the three-dimensional genome organization between malignant and benign prostate tissues, arguing for constraints to the three-dimensional genome of prostate tumours. Moreover, we identify structural variants as effectors of changes to focal chromatin interactions, guiding cis-regulatory element hijacking 2,3 that imposes opposing expression changes on genes found at antipodes of a rearrangement. This leads to the repression of tumour suppressor gene expression and up-regulation of oncogenes, such as at the TMPRSS2-ERG and PMEPA1-ZNF156 loci. Collectively, our results argue that cis-regulatory element hijacking by structural variants overshadows large-scale topological changes to alter gene regulation and promote oncogenesis.

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“…Incomplete fine-mapping efforts mean that most GWAS loci are not mapped to a single causal variant but rather include multiple variants in a credible set, each of which could potentially influence gene expression in a different cellular context. The typical step after finemapping involves attempts to connect the putatively causal variantsand the regulatory elements in which they resideto the genes they regulate, using methods such as cis-eQTL colocalization, single cell chromatin co-accessibility, and DNA proximity assays (such as HiC) [2][3][4][5] . These approaches however have limitations.…”

Section: Mainmentioning

confidence: 99%

A genome-wide CRISPR screen identifies regulators of beta cell function involved in type 2 diabetes risk

Navarro-Guerrero

Bevacqua

et al. 2021

Preprint

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Identification of the genes and processes mediating genetic association signals for complex disease represents a major challenge. Since many of the genetic signals for type 2 diabetes exert their effects through pancreatic islet-cell dysfunction, we performed a genome-wide pooled CRISPR loss-of-function screen in human pancreatic beta cells. We focused on the regulation of insulin content as a disease-relevant readout of beta cell function. We identified 580 genes influencing this phenotype: integration with genetic and genomic data provided experimental support for 20 candidate type 2 diabetes effector transcripts including the autophagy receptor CALCOCO2. Our study highlights how cellular screens can augment existing multi-omic efforts to accelerate biological and translational inference at GWAS loci.

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Genome-wide enhancer maps link risk variants to disease genes

Cited by 465 publications

References 77 publications

North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants

North Carolina Macular Dystrophy: Phenotypic Variability and Computational Analysis of Disease-Associated Noncoding Variants

Cis-regulatory Element Hijacking by Structural Variants Overshadows Higher-Order Topological Changes in Prostate Cancer

A genome-wide CRISPR screen identifies regulators of beta cell function involved in type 2 diabetes risk

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