The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

Long, Mark D.; Smiraglia, Dominic J.; Campbell, Moray J.

doi:10.3390/biom7010015

Cited by 83 publications

(66 citation statements)

References 157 publications

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“…Although a strictly linear relationship between GSDME methylation and expression is not anticipated, we would expect that increased methylation leads to decreased gene expression in cancer. The discrepancy in our results and in conflicting findings, make it hard to clearly define the effect of GSDME methylation on its expression, particularly in light of recent studies suggesting that the relation between the 2 could be more complex . One conflicting factor could be miRNAs (mir‐3p and mir26b‐5p) that are known to modulate GSDME expression, and another could be copy number variations (CNVs) that play an important role in complex phenotypes such as cancer .…”

Section: Discussioncontrasting

confidence: 63%

“…The discrepancy in our results and in conflicting findings, 13,30 make it hard to clearly define the effect of GSDME methylation on its expression, particularly in light of recent studies suggesting that the relation between the 2 could be more complex. 31 One conflicting factor could be miRNAs (mir-3p and mir26b-5p) that are known to modulate GSDME expression, 32 and another could be copy number variations (CNVs) that play an important role in complex phenotypes such as cancer. 33 Moreover, the location of CpG methylation (in or near the island) is crucial to its influence on gene expression such that CpGs located outside the islands have a bigger impact on gene expression than those located within.…”

Section: Discussionmentioning

confidence: 99%

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Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

et al. 2019

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In addition to its implication in hereditary hearing loss, the Gasdermin E ( GSDME ) gene is also a tumor suppressor involved in cancer progression through programmed cell death. GSDME epigenetic silencing through methylation has been shown in some cancer types, but studies are yet to fully explore its diagnostic/prognostic potential in colorectal cancer on a large‐scale. We used public data from The Cancer Genome Atlas (TCGA) to investigate differences in GSDME methylation and expression between colorectal cancer and normal colorectal tissue, and between left‐ and right‐sided colorectal cancers in 432 samples. We also explored GSDME 's diagnostic capacity as a biomarker for colorectal cancer. We observed differential methylation in all 22 GSDME CpGs between tumor and normal tissues, and in 18 CpGs between the left‐ and right‐sided groups. In the cancer tissue, putative promoter probes were hypermethylated and gene body probes were hypomethylated, while this pattern was inversed in normal tissues. Both putative promoter and gene body CpGs correlated well together but formed distinct methylation patterns with the putative promoter exhibiting the most pronounced methylation differences between tumor and normal tissues. Clinicopathological parameters, excluding age, did not show any effect on CpG methylation. Although the methylation of 5 distinct probes was a good predictor of gene expression, we could not identify an association between GSDME methylation and expression in general. Survival analysis showed no association between GSDME methylation and expression on 5‐year patient survival. Through logistic regression, we identified a combination of 2 CpGs, that can discriminate between cancer and normal tissue with high accuracy (AUC = 0.95) irrespective of age and tumor stage. We also validated our model in 3 external methylation datasets, from the Gene Expression Omnibus database, and similar results were reached. Our results suggest that GSDME is a promising biomarker for the detection of colorectal cancer.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

et al. 2019

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“…Methylation of the cytosine at CpG sites has important roles within the cell in regulating gene expression and silencing (Long et al, 2017). Single-gene and genome sequencing studies have identified that the vast majority of substitution mutations in human cancer occurs at the CpG dinucleotide (Cooper and Youssoufian, 1988;Esteller et al, 2001;Esteller, 2002;Poulos et al, 2017;Pfeifer, 2017).…”

Section: Discussionmentioning

confidence: 99%

Evolutionary forces on different flavors of intrinsic disorder in the human proteome

Forcelloni

Giansanti

2019

Preprint

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In this study, we perform a systematic analysis of evolutionary forces (i.e., mutational bias and natural selection) that shape the codon usage bias of human genes encoding for different structural and functional variants of proteins. Well-structured proteins are expected to be more under control by natural selection than intrinsically disordered proteins because one or few mutations (even synonymous) in the genes can result in a protein that no longer folds correctly. On the contrary, intrinsically disordered proteins are generally thought to evolve more rapidly than well-folded proteins, primarily attributed to relaxed purifying natural selection due to the lack of structural constraints. Using different genetic tools, we find compelling evidence that intrinsically disordered proteins are the variant of human proteins on which both mutational bias and natural selection act more effectively, corroborating their essential role for evolutionary adaptability and protein evolvability. We speculate that intrinsically disordered proteins have a high tolerance to mutations (both neutral and adaptive) but also a selective propensity to preserve their structural disorder, i.e., flexibility and conformational dynamics under physiological conditions. Additionally, we confirm not only that intrinsically disordered proteins are preferentially encoded by GC-rich genes, but also that they are characterized by the highest fraction of CpG-sites in the sequences, implying a higher susceptibility to methylation resulting in C-T transition mutations. Our results provide new insight about protein evolution and human genetic diseases identifying intrinsically disordered proteins as reservoirs for evolutionary innovations.

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“…Enhancer methylation has been correlated with gene expression, most frequently in cancer patients but also in healthy individuals [43]. Notably, enhancer methylation is both correlated with increased and decreased gene expression, possibly explaining why we see an enrichment of CpG deamination in both gain and loss of function events [44].…”

Section: Discussionmentioning

confidence: 79%

Functional Characterization of Enhancer Evolution in the Primate Lineage

Klein

Keith

Agarwal

et al. 2018

Preprint

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Background: Enhancers play an important role in morphological evolution and speciation by controlling the spatiotemporal expression of genes. Due to technological limitations, previous efforts to understand the evolution of enhancers in primates have typically studied many enhancers at low resolution, or single enhancers at high resolution. Although comparative genomic studies reveal large-scale turnover of enhancers, a specific understanding of the molecular steps by which mammalian or primate enhancers evolve remains elusive. Results:We identified candidate hominoid-specific liver enhancers from H3K27ac ChIP-seq data. After locating orthologs in 11 primates spanning ~40 million years, we synthesized all orthologs as well as computational reconstructions of 9 ancestral sequences for 348 "active tiles" of 233 putative enhancers. We concurrently tested all sequences (20 per tile) for regulatory activity with STARR-seq in HepG2 cells, with the goal of characterizing the evolutionary-functional trajectories of each enhancer. We observe groups of enhancer tiles with coherent trajectories, most of which can be explained by one or two mutational events per tile. We quantify the correlation between the number of mutations along a branch and the magnitude of change in functional activity. Finally, we identify 57 mutations that correlate with functional changes; these are enriched for cytosine deamination events within CpGs, compared to background events. Conclusions:We characterized the evolutionary-functional trajectories of hundreds of liver enhancers throughout the primate phylogeny. We observe subsets of regulatory sequences that appear to have gained or lost activity at various positions in the primate phylogeny. We use these data to quantify the relationship between sequence and functional divergence, and to identify CpG deamination as a potentially important force in driving changes in enhancer activity during primate evolution.

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The Genomic Impact of DNA CpG Methylation on Gene Expression; Relationships in Prostate Cancer

Cited by 83 publications

References 157 publications

Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

Evolutionary forces on different flavors of intrinsic disorder in the human proteome

Functional Characterization of Enhancer Evolution in the Primate Lineage

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