HEDD: Human Enhancer Disease Database

Wang, Zhen; Zhang, Quanwei; Zhang, Wen; Lin, Jhih Rong; Cai, Ying; Mitra, Joydeep; Zhang, Zhengdong D.

doi:10.1093/nar/gkx988

Cited by 56 publications

(52 citation statements)

References 65 publications

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“…Enhancer malfunction is emerging as a major contributor to human diseases, including cancer, as mounting evidence across many tumor types shows that enhancer networks are rewired by molecular aberrations that collectively lead to the cancer phenotype [21][22][23][24][25][26][27]. Translocations, deletions, and mutations within regulatory regions of the genome are frequently observed in cancer patients, which may cause loss of expression of tumor suppressors or overexpression of oncogenes [25,27,28].…”

Section: Introductionmentioning

confidence: 99%

Transcriptional control by enhancers and enhancer RNAs

2019

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The regulation of gene expression is a fundamental cellular process and its misregulation is a key component of disease. Enhancers are one of the most salient regulatory elements in the genome and help orchestrate proper spatiotemporal gene expression during development, in homeostasis, and in response to signaling. Notably, molecular aberrations at enhancers, such as translocations and single nucleotide polymorphisms, are emerging as an important source of human variation and susceptibility to disease. Herein we discuss emerging paradigms addressing how genes are regulated by enhancers, common features of active enhancers, and how non-coding enhancer RNAs (eRNAs) can direct gene expression programs that underlie cellular phenotypes. We survey the current evidence, which suggests that eRNAs can bind to transcription factors, mediate enhancer-promoter interactions, influence RNA Pol II elongation, and act as decoys for repressive cofactors. Furthermore, we discuss current methodologies for the identification of eRNAs and novel approaches to elucidate their functions.

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Section: Introductionmentioning

confidence: 99%

Transcriptional control by enhancers and enhancer RNAs

2019

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“…Accordingly, thousands of enhancers in different model animals such as fruit fly, nematode and mouse, as well as human have been annotated by different international genome annotation consortia, such as ENCODE, NIH Epigenome Roadmap, FANTOM5, and Blueprint/IHEC . At the same time, enhancer related databases such as VISTA Enhancer Browser, Enhancer Atlas, and HEDD have been developed for visualizing and sharing information of enhancers annotations across mammalians. These useful resources provide new insight into their roles and mechanism of enhancers‐mediated gene regulation.…”

Section: Enhancer Is a Positive Regulator In Transcriptionmentioning

confidence: 99%

Enhancer and super‐enhancer: Positive regulators in gene transcription

Peng

Zhang

2018

Anim Models and Exp Med

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Enhancer is a positive regulator for spatiotemporal development in eukaryotes. As a cluster, super‐enhancer is closely related to cell identity‐ and fate‐determined processes. Both of them function tightly depending on their targeted transcription factors, cofactors, and genes through distal genomic interactions. They have been recognized as critical components and played positive roles in transcriptional regulatory network or factory. Recent advances of next‐generation sequencing have dramatically expanded our ability and knowledge to interrogate the molecular mechanism of enhancer and super‐enhancer for transcription. Here, we review the history, importance, advances and challenges on enhancer and super‐enhancer field. This will benefit our understanding of their function mechanism for transcription underlying precise gene expression.

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“…Mutations (single nucleotide variants (SNVs), short insertions and deletions (indels) and structural variants (SVs)) at enhancers with high LoF-tolerance are less likely to produce fitness defects while variants at enhancers with low tolerance to LoF are more likely to be disease-causing. Such prioritization scheme will not only help understand the causal variants of Mendelian diseases, it will also provide insights for the many non-coding susceptibility loci found by genome-wide association studies (GWAS) [27][28][29][30][31] of which the potential causations beneath the associations are still unknown.…”

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confidence: 99%

Loss-of-function tolerance of enhancers in the human genome

Gökçümen

Khurana

2020

PLoS Genet

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Previous studies have surveyed the potential impact of loss-of-function (LoF) variants and identified LoF-tolerant protein-coding genes. However, the tolerance of human genomes to losing enhancers has not yet been evaluated. Here we present the catalog of LoF-tolerant enhancers using structural variants from whole-genome sequences. Using a conservative approach, we estimate that individual human genomes possess at least 28 LoF-tolerant enhancers on average. We assessed the properties of LoF-tolerant enhancers in a unified regulatory network constructed by integrating tissue-specific enhancers and gene-gene interactions. We find that LoF-tolerant enhancers tend to be more tissue-specific and regulate fewer and more dispensable genes relative to other enhancers. They are enriched in immune-related cells while enhancers with low LoF-tolerance are enriched in kidney and brain/neuronal stem cells. We developed a supervised learning approach to predict the LoFtolerance of all enhancers, which achieved an area under the receiver operating characteristics curve (AUROC) of 98%. We predict 3,519 more enhancers would be likely tolerant to LoF and 129 enhancers that would have low LoF-tolerance. Our predictions are supported by a known set of disease enhancers and novel deletions from PacBio sequencing. The LoF-tolerance scores provided here will serve as an important reference for disease studies. Author summaryEnhancers are elements where transcription factors bind and regulate the expression of protein-coding genes. Although multiple previous studies have focused on which genes can tolerate loss-of-function (LoF), none has systematically evaluated the tolerance of all enhancers in the human genome to LoF. Individual studies have shown a broad range of phenotypic effects of enhancer LoF. The phenotypic effects of enhancer LoF likely fall into a spectrum where deletion of LoF-tolerant enhancers would not elicit substantial phenotypic impact, while some enhancers are likely to cause fitness defects when deleted. Here PLOS GENETICSPLOS Genetics | https://doi.

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HEDD: Human Enhancer Disease Database

Cited by 56 publications

References 65 publications

Transcriptional control by enhancers and enhancer RNAs

Transcriptional control by enhancers and enhancer RNAs

Enhancer and super‐enhancer: Positive regulators in gene transcription

Loss-of-function tolerance of enhancers in the human genome

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