dbSUPER: a database of super-enhancers in mouse and human genome

Khan, Aziz; Zhang, Xuegong

doi:10.1093/nar/gkv1002

Cited by 365 publications

(314 citation statements)

References 51 publications

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“…A particularly active subset of REs is situated in super-enhancers (SEs). SEs are large clusters of enhancer elements which show high association for Mediator occupancy and histone H3K27Ac modifications, and they show more tissue specific activity than enhancers in general [12–14]. As we and others have reported, we found that candidate risk SNPs often overlap SEs, and may especially affect disease predisposition.…”

Section: Resultssupporting

confidence: 66%

Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes

Pierce

Coetzee

2017

PLoS ONE

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Genome-wide association studies (GWAS) have linked dozens of single nucleotide polymorphisms (SNPs) with Parkinson’s disease (PD) risk. Ascertaining the functional and eventual causal mechanisms underlying these relationships has proven difficult. The majority of risk SNPs, and nearby SNPs in linkage disequilibrium (LD), are found in intergenic or intronic regions and confer risk through allele-dependent expression of multiple unknown target genes. Combining GWAS results with publicly available GTEx data, generated through eQTL (expression quantitative trait loci) identification studies, enables a direct association of SNPs to gene expression levels and aids in narrowing the large population of potential genetic targets for hypothesis-driven experimental cell biology. Separately, overlapping of SNPs with putative enhancer segmentations can strengthen target filtering. We report here the results of analyzing 7,607 PD risk SNPs along with an additional 23,759 high linkage disequilibrium-associated variants paired with eQTL gene expression. We found that enrichment analysis on the set of genes following target filtering pointed to a single large LD block at 6p21 that contained multiple HLA-MHC-II genes. These MHC-II genes remain associated with PD when the genes were filtered for correlation between GWAS significance and eQTL levels, strongly indicating a direct effect on PD etiology.

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Section: Resultssupporting

confidence: 66%

Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes

Pierce

Coetzee

2017

PLoS ONE

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“…Accordingly, this region matches an S-E domain predicted by profiling K27ac ChIP-seq signals in the interactive database DBsuper [101] (Figure S11). Integrating ChIP-seq signals for additional trans-factors (such as Mediator complex, BRD4 and RNA Pol II) and active histone marks (e.g., K4me2/3) may strengthen such S-E predictions [102].…”

Section: Resultssupporting

confidence: 57%

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Cellier

2017

Biology

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NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs). Analyses establish that NRAMP1 is part of an autonomous topologically associated domain delimited by ubiquitous CCCTC-binding factor (CTCF) sites. NRAMP1 locus contains five regulatory regions: a predicted super-enhancer (S-E) key to phagocyte-specific expression; the proximal promoter; two intronic areas, including 3′ inhibitory elements that restrict expression during development; and a block of upstream sites possibly extending the S-E domain. Also the downstream region adjacent to the 3′ CTCF locus boundary may regulate expression during hematopoiesis. Mobilization of the locus 14 predicted transcriptional regulatory elements occurs in three steps, beginning with hematopoiesis; at the onset of myelopoiesis and through myelo-monocytic differentiation. Basal expression level in mature phagocytes is further influenced by genetic variation, tissue environment, and in response to infections that induce various epigenetic memories depending on microorganism nature. Constitutively associated transcription factors (TFs) include CCAAT enhancer binding protein beta (C/EBPb), purine rich DNA binding protein (PU.1), early growth response 2 (EGR2) and signal transducer and activator of transcription 1 (STAT1) while hypoxia-inducible factors (HIFs) and interferon regulatory factor 1 (IRF1) may stimulate iron acquisition in pro-inflammatory conditions. Mouse orthologous locus is generally conserved; chromatin patterns typify a de novo myelo-monocytic gene whose expression is tightly controlled by TFs Pu.1, C/ebps and Irf8; Irf3 and nuclear factor NF-kappa-B p 65 subunit (RelA) regulate expression in inflammatory conditions. Functional differences in the determinants identified at these orthologous loci imply that species-specific mechanisms control gene expression.

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“…To investigate this hypothesis using our dataset, we overlaid the genomic positions with a database of 65,950 super enhancers across 107 tumor and normal cell types 26 . In the majority of TERTp structural variants (65%), at least one predicted super enhancer was found to directly overlap with the juxtaposed position (Supplementary Table 3).…”

Section: Resultsmentioning

confidence: 99%

Systematic analysis of telomere length and somatic alterations in 31 cancer types

et al. 2017

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Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Tumor telomeres were shorter compared to normal tissues, and longer in sarcomas and gliomas compared to other cancers. Amongst 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications, and transcript fusions, and predicted telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, mostly with undetectable TERT, harbored ATRX or DAXX alterations, demonstrated elongated telomeres and increased telomeric repeat containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT, nor harbored alterations in ATRX/DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.

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dbSUPER: a database of super-enhancers in mouse and human genome

Cited by 365 publications

References 51 publications

Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes

Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes

Developmental Control of NRAMP1 (SLC11A1) Expression in Professional Phagocytes

Systematic analysis of telomere length and somatic alterations in 31 cancer types

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