Towards a comprehensive catalogue of validated and target-linked human enhancers

Gasperini, Molly; Tome, Jacob M.; Shendure, Jay

doi:10.1038/s41576-019-0209-0

“…CRISPR activator (CRISPRa) or inhibitor (CRISPRi) versions of dCas9 have been generated by fusion with repressor or activator domains (such as KRAB or VP64 respectively) allowing to assess the function of putative GREs in selected loci (Pulecio et al 2017). Both classical Cas9 knockin/knockout as well as CRISPRa and CRISPRi are already used in targeted applications and in screening approaches where large genomic regions are interrogated for putative enhancer elements (Fulco et al 2016;Gasperini et al 2020). A database for CRISPR/Cas9 screens has been established (Rauscher et al 2017).…”

Section: Tools To Test Non-coding Variantsmentioning

confidence: 99%

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

Ohnmacht

¹

,

Sinkkonen

²

,

Krüger

³

2020

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Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease-and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future.

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“…The ultimate goal is to create a comprehensive catalog of functionally supported human regulatory elements that are well annotated in terms of the cell types, active regulatory elements, the genes that each element regulates, and the degree of activation of each element. 44…”

Section: Future Directions and Limitationsmentioning

confidence: 99%

Human library of cardiac promoters and enhancers

Deviatiiarov

¹

,

Gams

²

,

Syunyaev

³

et al. 2020

Preprint

0

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Genome regulatory elements play a critical role during cardiac development and maintenance of normal physiological homeostasis, and genome-wide association studies identified a large number of SNPs associated with cardiovascular diseases localized in intergenic zones. We used cap analysis of gene expression (CAGE) to identify transcription start sites (TSS) with one nucleotide resolution that effectively maps genome regulatory elements in a representative collection of human heart tissues. Here we present a comprehensive and fully annotated CAGE atlas of human promoters and enhancers from four chambers of the non-diseased human donor hearts, including both atria and ventricles. We have identified 10,528 novel regulatory elements, where 2,750 are classified as TSS and 4,258 novel enhancers, which were validated with ChIP-seq libraries and motif enrichment analysis. We found that heart-region specific expression patterns are primarily based on the alternative promoter and specific enhancer activity. Our study significantly increased evidence of the association of regulatory elements-located variants with heart morphology and pathologies. The precise location of cardiac disease-related SNPs within the regulatory regions and their correlation with a specific cell type offers a new understanding of genetic heart diseases.

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“…The ultimate goal is to create a comprehensive catalog of functionally supported human regulatory elements that are well annotated in terms of the cell types, active regulatory elements, the genes that each element regulates, and the degree of activation of each element. 44 Online Methods…”

Section: Future Directions and Limitationsmentioning

confidence: 99%

Human atlas of cardiac promoters and enhancers reveals important role of regulatory elements in heritable diseases

Deviatiiarov

¹

,

Gams

²

,

Syunyaev

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

Genome regulatory elements play a critical role during cardiac development and maintenance of normal physiological homeostasis, and genome-wide association studies identified a large number of SNPs associated with cardiovascular diseases localized in intergenic zones. We used cap analysis of gene expression (CAGE) to identify transcription start sites (TSS) with one nucleotide resolution that effectively maps genome regulatory elements in a representative collection of human heart tissues. Here we present a comprehensive and fully annotated CAGE atlas of human promoters and enhancers from four chambers of the non-diseased human donor hearts, including both atria and ventricles. We have identified 10,528 novel regulatory elements, where 2,750 are classified as TSS and 4,258 novel enhancers, which were validated with ChIP-seq libraries and motif enrichment analysis. We found that heart-region specific expression patterns are primarily based on the alternative promoter and specific enhancer activity. Our study significantly increased evidence of the association of regulatory elements-located variants with heart morphology and pathologies. The precise location of cardiac disease-related SNPs within the regulatory regions and their correlation with a specific cell type offers a new understanding of genetic heart diseases.

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Towards a comprehensive catalogue of validated and target-linked human enhancers

Cited by 273 publications

References 233 publications

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

Missing heritability in Parkinson’s disease: the emerging role of non-coding genetic variation

Human library of cardiac promoters and enhancers

Human atlas of cardiac promoters and enhancers reveals important role of regulatory elements in heritable diseases

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