Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome

Cohen, Andrea J.; Saiakhova, Alina; Corradin, Olivia; Luppino, Jennifer M.; Lovrenert, Katreya; Bartels, Cynthia F.; Morrow, James J.; Mack, Stephen C.; Dhillon, Gursimran; Beard, Lydia; Myeroff, Lois; Kalady, Matthew F.; Willis, Joseph E.; Bradner, James E.; Keri, Ruth A.; Berger, Nathan A.; Pruett-Miller, Shondra M.; Markowitz, Sanford D.; Scacheri, Peter C.

doi:10.1038/ncomms14400

Cited by 110 publications

(144 citation statements)

References 76 publications

(109 reference statements)

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“…These sites were either "gained" or "lost" in the metastatic cells relative to their matched controls. These metastasis-associated gains and losses of the H3K4me1 signal were reminiscent of those that we previously identified in the setting of primary tumor development through comparisons of primary colon tumors and normal colon tissue, known as VELs 12,13 . In distinction, we now and herein term the regions that show differential enrichment of H3K4me1 between metastatic samples and non-metastatic controls Metastatic Variant Enhancer…”

Section: The Metastatic Phenotype Of Human Osteosarcoma Is Associatedsupporting

confidence: 59%

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Positively Selected Enhancer Elements Endow Tumor Cells with Metastatic Competence

Bayles

et al. 2017

Preprint

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Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic tumors in human patients as well as nearisogenic pairs of high and low lung-metastatic osteosarcoma cells. We term

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Section: The Metastatic Phenotype Of Human Osteosarcoma Is Associatedsupporting

confidence: 59%

“…Previous studies by our group have demonstrated that malignant transformation is accompanied by locus-specific gains and losses in enhancer activity across the epigenome. We previously termed these Variant Enhancer Loci (VELs) 12,13 .…”

Section: Introductionmentioning

confidence: 99%

Positively Selected Enhancer Elements Endow Tumor Cells with Metastatic Competence

Bayles

et al. 2017

Preprint

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“…Super enhancers are found across diverse cell types [70,71,75], they contain high levels of H3K27ac, are occupied by enhancer-associated proteins, such as Mediator and RNA Pol II, they are cell type-specific, and regulate the genes controlling cell state. Tumor cells often acquire super enhancers near oncogenes [76,77], and super enhancers are also remarkably enriched for GWAS identified SNPs that associate to several common diseases [78]. Some of the training data enhancers defined in this work might reside at the super enhancers.…”

Section: Discussionmentioning

confidence: 99%

Enhancer prediction in the human genome by probabilistic modelling of the chromatin feature patterns

Osmala

Lähdesmäki

2019

Preprint

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Background: The human genome is far from completely annotated. Specifically, the locations ofgenedistal regulatory enhancers are difficult to locate. Enhancers are binding sites of transcription factors and occupied by nucleosomes with modified histones. The binding sites of transcription factors (TFs) and the localization of histone modifications can be quantified by the chromatin immunoprecipitation assay coupled with next generation sequencing (ChIP-seq). The resulting data has been successfully adopted for genomewide enhancer identification by several unsupervised and supervised machine learning methods. However, the current methods predict different numbers and different sets of enhancers for the same cell type, and they do not utilize the pattern of the ChIP-seq coverage profiles efficiently. It is also difficult to estimate the accuracy and specificity of the genome-wide enhancer predictions. Results:We developed PREPRINT, a PRobabilistic Enhancer PRedictIoN Tool. We considered the pattern of, for example, the ChIP-seq coverage profile around the enhancers. The data at the positive and negative examples of enhancers was utilized to probabilistically model the enhancer coverage pattern and to train a kernel-based classifier. We demonstrated the performance of the method using ENCODE data from two cell lines. The predicted enhancers were computationally validated based on the TFs and co-regulatory factor binding sites. We compared our enhancer predictions to the ones obtained by other methods. The effects of different parameter choices during training, testing and validation were studied, and finally, the approach to validate the genome-wide predictions was investigated. Conclusion: PREPRINT performed comparably to the state-of-the-art methods and provided probabilistic interpretation (i.e. uncertainty) for the predictions. PREPRINT generalized to data from cell type not utilized for training, and often the performance of PREPRINT was superior to RFECS. We observed that the choice of training data and the choice of parameter values at different steps of the enhancer prediction and validation influenced on the final set of predictions. PREPRINT identifed biologically validated enhancers not predicted by the competing methods. The enhancers predicted by PREPRINT can aid the genome interpretation in functional genomics and clinical studies.

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“…Epigenetic marks (or epigenotype) provide information on aberrant genomic hypomethylation and occasional transcriptional silencing by hypermethylation of selected genes normally unmethylated. The epigenotype also includes chromatin alterations and dysregulation of noncoding RNAs, which are becoming increasingly apparent threats for genome stability and significant contributors to initiation and progression of colorectal and noncolorectal carcinogenesis . Two facts in favor of the carcinogenic importance of epigenetic DNA modifications are that eventually all CRC contain a methylome characterized by hundreds to thousands of prominently aberrant methylated genes, and that more than 10% of the protein‐coding genes exhibit alterations in their methylation status .…”

Section: Melatonin and Epigenome: The Fight Against Crc In The New Eramentioning

confidence: 99%

“…The epigenotype also includes chromatin alterations and dysregulation of noncoding RNAs, which are becoming increasingly apparent threats for genome stability and significant contributors to initiation and progression of colorectal and noncolorectal carcinogenesis. 260,261 Two facts in favor of the carcinogenic importance of epigenetic DNA modifications are that eventually all CRC contain a methylome characterized by hundreds to thousands of prominently aberrant methylated genes, and that more than 10% of the protein-coding genes exhibit alterations in their methylation status. 262 Accumulated evidence indicates that epigenetic aberrations robustly influence either the prognosis and therapeutic responses of the CRC patients, such as has been reported for the radiosensitivity of human HTC116 CRC cells.…”

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confidence: 99%

The emergence of melatonin in oncology: Focus on colorectal cancer

Gil‐Martín

Egea

Reíter

et al. 2019

Medicinal Research Reviews

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Within the last few decades, melatonin has increasingly emerged in clinical oncology as a naturally occurring bioactive molecule with substantial anticancer properties and a pharmacological profile optimal for joining the currently available pharmacopeia. In addition, extensive experimental data shows that this chronobiotic agent exerts oncostatic effects throughout all stages of tumor growth, from initial cell transformation to mitigation of malignant progression and metastasis; additionally, melatonin alleviates the side effects and improves the welfare of radio/chemotherapy‐treated patients. Thus, the support of clinicians and oncologists for the use of melatonin in both the treatment and proactive prevention of cancer is gaining strength. Because of its epidemiological importance and symptomatic debut in advanced stages of difficult clinical management, colorectal cancer (CRC) is a preferential target for testing new therapies. In this regard, the development of effective forms of clinical intervention for the improvement of CRC outcome, specifically metastatic CRC, is urgent. At the same time, the need to reduce the costs of conventional anti‐CRC therapy results is also imperative. In light of this status quo, the therapeutic potential of melatonin, and the direct and indirect critical processes of CRC malignancy it modulates, have aroused much interest. To illuminate the imminent future on CRC research, we focused our attention on the molecular mechanisms underlying the multiple oncostatic actions displayed by melatonin in the onset and evolution of CRC and summarized epidemiological evidence, as well as in vitro, in vivo and clinical findings that support the broadly protective potential demonstrated by melatonin.

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Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome

Cited by 110 publications

References 76 publications

Positively Selected Enhancer Elements Endow Tumor Cells with Metastatic Competence

Positively Selected Enhancer Elements Endow Tumor Cells with Metastatic Competence

Enhancer prediction in the human genome by probabilistic modelling of the chromatin feature patterns

The emergence of melatonin in oncology: Focus on colorectal cancer

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