A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker

Bozhilov, Yavor; Downes, Damien J.; Telenius, Jelena; Oudelaar, A. Marieke; Olivier, Emmanuel; Mountford, Joanne C.; Hughes, Jim R.; Gibbons, Richard J.; Higgs, Douglas R.

doi:10.1038/s41467-021-23980-6

Cited by 23 publications

(13 citation statements)

References 52 publications

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“…2 ). Machine-learning approaches have proven accurate at predicting allele-specific changes in transcription factor binding and chromatin accessibility 31 , 32 , including for de novo gain-of-function changes 33 . We have previously developed a machine-learning model, deepHaem 19 , which uses 694 DNase I hypersensitivity and ATAC-seq datasets to predict changes to active regulatory elements.…”

Section: Resultsmentioning

confidence: 99%

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

et al. 2021

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The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies (GWAS) identified the 3p21.31 region as conferring a two-fold increased risk of respiratory failure. Here, using a combined multiomics and machine-learning approach, we identify the gain-of-function risk A allele of a single-nucleotide polymorphism (SNP), rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, Leucine Zipper Transcription Factor Like 1 ( LZTFL1 ). Selective spatial transcriptomic analysis of COVID-19 patient lung biopsies shows the presence of signals associated with epithelial-mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1 . We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely to be responsible for the 3p21.31 associated risk. As the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may provide a therapeutic target.

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Section: Resultsmentioning

confidence: 99%

“…Positive scores (loss-of-function) were adjusted to zero. In general, variants generating de novo regulatory elements 33 have scores lower than – 0.1, which was not true for any variant in any cell type.…”

Section: Extended Datamentioning

confidence: 88%

Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

et al. 2021

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“…In these guidelines, we have primarily discussed variants that impact existing regulatory regions; however, there are examples of disease-causing variants that act through creating novel regulatory elements. For example, a recent paper discussed a SNV that created a new promoter leading to dysregulation of genes in the human α-globin locus [ 86 ]. We have also not discussed variants in non-coding genes in detail; however, we note examples of identified pathogenic variants in this area of active research (Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

Recommendations for clinical interpretation of variants found in non-coding regions of the genome

et al. 2022

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Background The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. Methods We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. Results We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants. Conclusions These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.

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“…In all cases tested, the gene lying closest to the SE is expressed at higher levels than the adjacent gene, which is in turn expressed at higher levels than the next copy and so on [67][68][69][70] . A natural mutation which creates a new promoter lying between the super-enhancer and the a-globin genes downregulates a-globin expression, whereas placing this promoter upstream of the super-enhancer, has little effect on a-globin expression 71 . Together these observations suggest that the orientation dependence of the super-enhancer might, at least in part, involve a directional tracking mechanism by which the enhancers and promoters interact.…”

Section: Discussionmentioning

confidence: 99%

Multipartite super-enhancers function in an orientation-dependent manner

Kassouf

Francis

Gosden

et al. 2022

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Transcriptional enhancers regulate gene expression in a developmental-stage and cell-specific manner. They were originally defined as individual regulatory elements that activate expression regardless of distance and orientation to their cognate genes. Genome-wide studies have shown that the mammalian enhancer landscape is much more complex, with different classes of individual enhancers and clusters of enhancer-like elements combining in additive, synergistic and redundant manners, possibly acting as single, integrated regulatory elements. These so-called super-enhancers are largely defined as clusters of enhancer-like elements which recruit particularly high levels of Mediator and often drive high levels of expression of key lineage-specific genes. Here, we analysed 78 erythroid-specific super-enhancers and showed that, as units, they preferentially interact in a directional manner, to drive expression of their cognate genes. Using the well characterised α -globin super-enhancer, we show that inverting this entire structure severely downregulates α -globin expression and activates flanking genes 5' of the super-enhancer. Our detailed genetic dissection of the α -globin locus clearly attributes the cluster's functional directionality to its sequence orientation, demonstrating that, unlike regular enhancers, super-enhancers act in an orientation-dependent manner. Together, these findings identify a novel emergent property of super-enhancers and revise current models by which enhancers are thought to contact and activate their cognate genes.

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A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker

Cited by 23 publications

References 52 publications

Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Multipartite super-enhancers function in an orientation-dependent manner

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