Pleiotropic Enhancers are Ubiquitous Regulatory Elements in the Human Genome

Laiker, Ian; Frankel, Nicolás

doi:10.1093/gbe/evac071

Cited by 12 publications

(3 citation statements)

References 50 publications

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“…Particularly, the 1st active enhancer of CDH1 chr16: 68732016-68732406 (hg38 version), was detected to interact with the promoter regions (also a CGI region) of CDH1 https://pressto.binf.ku.dk/about.php#h_enhancers_description_long . In addition, Activity By Contact (ABC) enhancer study [ 60 ] further identified that most of them are “pleiotropic” enhancers where enhancers were detected to be contacted with multiple genes in different cell-line or tissues [ 61 ]. Additional file 1 : Fig.…”

Section: Methodsmentioning

confidence: 99%

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease

de Ponthaud,

Abdalla,

Belot

et al. 2024

Clin Epigenet

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Background E-cadherin, a major actor of cell adhesion in the intestinal barrier, is encoded by the CDH1 gene associated with susceptibility to Crohn Disease (CD) and colorectal cancer. Since epigenetic mechanisms are suspected to contribute to the multifactorial pathogenesis of CD, we studied CpG methylation at the CDH1 locus. The methylation of the CpG island (CGI) and of the 1st enhancer, two critical regulatory positions, was quantified in surgical specimens of inflamed ileal mucosa and in peripheral blood mononuclear cells (PBMC) of 21 CD patients. Sixteen patients operated on for a non-inflammatory bowel disease, although not normal controls, provided a macroscopically normal ileal mucosa and PBMC for comparison. Results In ileal mucosa, 19/21 (90%) CD patients vs 8/16 control patients (50%) (p < 0.01) had a methylated CDH1 promoter CGI. In PBMC, CD patients with methylated CGI were 11/21 (52%) vs 7/16 controls (44%), respectively. Methylation in the 1st enhancer of CDH1 was also higher in the CD group for each of the studied CpGs and for their average value (45 ± 17% in CD patients vs 36 ± 17% in controls; p < 0.001). Again, methylation was comparable in PBMC. Methylation of CGI and 1st enhancer were not correlated in mucosa or PBMC. Conclusions Methylation of several CpGs at the CDH1 locus was increased in the inflamed ileal mucosa, not in the PBMC, of CD patients, suggesting the association of CDH1 methylation with ileal inflammation. Longitudinal studies will explore if this increased methylation is a risk marker for colorectal cancer.

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Section: Methodsmentioning

confidence: 99%

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease

de Ponthaud,

Abdalla,

Belot

et al. 2024

Clin Epigenet

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“…Alternatively, identified enhancers that drove expression in multiple imaginal discs may simply represent pleiotropic enhancers. Enhancer pleiotropy is not uncommon (50, 51), and moreover, there is overlap in the enhancer content of our training sets for the various discs. There are many gene expression and developmental similarities among the discs, and likely significant regulatory overlap; chromatin profiling experiments have found that wing, leg, and eye discs share the majority of their regions of accessible chromatin (18, 32).…”

Section: Discussionmentioning

confidence: 99%

Regulatory genome annotation of 33 insect species

Asma,

Tieke,

Deem

et al. 2024

Preprint

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Annotation of newly-sequenced genomes frequently includes genes, but rarely covers important non-coding genomic features such as the cis-regulatory modules--e.g., enhancers and silencers--that regulate gene expression. Here, we begin to remedy this situation by developing a workflow for rapid initial annotation of insect regulatory sequences, and provide a searchable database resource with enhancer predictions for 33 genomes. Using our previously-developed SCRMshaw computational enhancer prediction method, we predict over 2.8 million regulatory sequences along with the tissues where they are expected to be active, in a set of insect species ranging over 360 million years of evolution. Extensive analysis and validation of the data provides several lines of evidence suggesting that we achieve a high true-positive rate for enhancer prediction. One, we show that our predictions target specific loci, rather than random genomic locations. Two, we predict enhancers in orthologous loci across a diverged set of species to a significantly higher degree than random expectation would allow. Three, we demonstrate that our predictions are highly enriched for regions of accessible chromatin. Four, we achieve a validation rate in excess of 70% using in vivo reporter gene assays. As we continue to annotate both new tissues and new species, our regulatory annotation resource will provide a rich source of data for the research community and will have utility for both small-scale (single gene, single species) and large-scale (many genes, many species) studies of gene regulation. In particular, the ability to search for functionally-related regulatory elements in orthologous loci should greatly facilitate studies of enhancer evolution even among distantly related species.

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“…As cis-regulatory DNA elements in eukaryotes, enhancers bind tissue-specific transcription factors (TFs) and specifically transmit regulatory information to their target gene promoters, participating in transcriptional regulation [ 17 , 18 ]. Through continuous research and accumulated datasets, scientists have realized that the number of enhancers is far greater than the number of genes [ 19 , 20 , 21 ]. Enhancer-mediated transcriptional regulation is tightly correlated with spatiotemporal gene expression patterns.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Role of Enhancer-Mediated Transcriptional Regulation in Precision Biology

Wang

Liu

Luo

et al. 2023

IJMS

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The emergence of precision biology has been driven by the development of advanced technologies and techniques in high-resolution biological research systems. Enhancer-mediated transcriptional regulation, a complex network of gene expression and regulation in eukaryotes, has attracted significant attention as a promising avenue for investigating the underlying mechanisms of biological processes and diseases. To address biological problems with precision, large amounts of data, functional information, and research on the mechanisms of action of biological molecules is required to address biological problems with precision. Enhancers, including typical enhancers and super enhancers, play a crucial role in gene expression and regulation within this network. The identification and targeting of disease-associated enhancers hold the potential to advance precision medicine. In this review, we present the concepts, progress, importance, and challenges in precision biology, transcription regulation, and enhancers. Furthermore, we propose a model of transcriptional regulation for multi-enhancers and provide examples of their mechanisms in mammalian cells, thereby enhancing our understanding of how enhancers achieve precise regulation of gene expression in life processes. Precision biology holds promise in providing new tools and platforms for discovering insights into gene expression and disease occurrence, ultimately benefiting individuals and society as a whole.

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Pleiotropic Enhancers are Ubiquitous Regulatory Elements in the Human Genome

Cited by 12 publications

References 50 publications

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease

Regulatory genome annotation of 33 insect species

Exploring the Role of Enhancer-Mediated Transcriptional Regulation in Precision Biology

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