Biological significance of genome‐wide DNA methylation profiles in keloids

Jones, Lamont; Greene, Joshua B.; Chen, Kangmei; Divine, George; Chitale, Dhananjay; Shah, Veena; Datta, Indrani; Worsham, Maria J.

doi:10.1002/lary.26063

Cited by 22 publications

(29 citation statements)

References 43 publications

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“…Differences in DNA methylation patterns from keloid scar and healthy tissue and cell samples have been demonstrated in a number of recent studies. Jones et al . carried out genome‐wide profiling using the Infinium HumanMethylation450 BeadChip and examined genes most differentially methylated between six keloid and six normal skin samples using a three‐tiered approach.…”

Section: Epigenetic Mechanisms In Keloid Scarringmentioning

confidence: 99%

From genetics to epigenetics: new insights into keloid scarring

Deng

Alghamdi

et al. 2017

Cell Proliferation

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Keloid scarring is a dermal fibroproliferative response characterized by excessive and progressive deposition of collagen; aetiology and molecular pathology underlying keloid formation and progression remain unclear. Genetic predisposition is important in the pathogenic processes of keloid formation, however, environmental factors and epigenetic mechanisms may also play pivotal roles. Epigenetic modification is a recent area of investigation in understanding the molecular pathogenesis of keloid scarring and there is increasing evidence that epigenetic changes may play a role in induction and persistent activation of fibroblasts in keloid scars. Here we have reviewed three epigenetic mechanisms: DNA methylation, histone modification and the role of non-coding RNAs. We also review the evidence that these mechanisms may play a role in keloid formation - in future, it may be possible that epigenetic markers may be used instead of prognostic or diagnostic markers here. However, there is a significant amount of work required to increase our current understanding of the role of epigenetic modification in keloid disease.

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Section: Epigenetic Mechanisms In Keloid Scarringmentioning

confidence: 99%

From genetics to epigenetics: new insights into keloid scarring

Deng

Alghamdi

et al. 2017

Cell Proliferation

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“…However, we cannot detect C1orf109 protein expression in indicated cells ( Fig EV1C). A previous study showed that C1orf109 expression was not observed in various types of abnormal cells, such as keloids, mainly because of hyper-methylation in the promoter region of the C1orf109 gene [14].…”

Section: C1orf109l-egfp Expression Inhibits Cell Growth In Vitro and mentioning

confidence: 97%

C1orf109L promote R-loop accumulation induced DNA damage to inhibit cell growth

Dou

Xie

et al. 2019

Preprint

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As a function unknown gene, C1orf109 is lower expression in various cells. Here, we reported that C1orf109L, the longest variant of C1orf109, which interacted with R-loop-regulating proteins to trigger R-loop, a three-stranded nucleic acid structure frequently mediated genome instability, accumulation. C1orf109L induce chronic DNA damage to promote P21 upregulation and strongly inhibits cell growth in vitro and in vivo by arresting the cell cycle in the G2 phase. With camptothecin (CPT), an R-loop activator, treatment, C1orf109L further triggers R-loop accumulation-induced DNA damage and promotes cell death by activating cell-death pathway. Furthermore, CPT treatment increases C1orf109L ubiquitination and turnover, which inhibits cell death and promotes the G0/G1 phase of the cell cycle. Therefore, our data illustrated the mechanisms underlying C1orf109L-related cell growth inhibition and provide feasibility and limitations for C1orf109L as a potential target for cancer therapy. Cell proliferation depends on the cell cycle. In abnormal cells, such as benign tumor cells and cancer cells, cell-cycle dis-regulation promotes cell growth [1]. For the cancer therapy strategies are mainly to kill cancer cell or inhibit cancer cell growth. Inducing cancer cell DNA damage is an efficient way to induce cancer cell death or growth inhibition. When genomic DNA is damaged, many pathways involved in cell-cycle regulation are activated, the most important of which involves activation of the DNA-damage checkpoint to arrest the cell cycle at different stages, including G1, S, and G2/M, which ensures that the damaged cell has enough time to repair DNA damage [2,3]. If DNA damage is so severe or the rate of damage is faster than the rate of the repairing process, then the cellular-death pathway is activated [4]. Among the DNA-damage checkpoints, the G1 and G2/M checkpoint restricts mitosis onset in response to multiple exogenous and endogenous factors [5]. With respect to endogenous factors, several proteins act as RNA-processing regulators that control the cell's fate, while dysfunction of RNA-processing-related proteins could trigger R-loop accumulation, and RNA-DNA hybrids can lead to DNA damage and induce-cell cycle arrest, which is an important factor for genome instability in abnormal cells, especially in cancer cells [6,7]. The R-loop also controls gene expression [8] and immunoglobulin (Ig)G class switching [9]. However, the regulation of R-loop proteins is poorly explored. Thus, in this study, we identified the novel gene, c1orf109, which is downregulated in a variety of cell lines. C1orf109L-eGFP expression triggers R-loop accumulation to induce DNA damage and arrest the cell cycle. We report that C1orf109L interacted with R-loop associated proteins and located on R-loops. C1orf109L overexpression that triggered R-loop accumulation no matter with or without CPT treatment in cells. The accumulated R-loops induced DNA damage which inhibits cell growth in vitro and in vivo. In terms of the mechanism underlying cell growth, t...

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“…Methylation of the DNA is essential during early normal development and contributes to the natural phenotypic variation in humans [ 15 , 16 ]. The aberrant addition (hypermethylation), or removal (hypomethylation) of the methyl group can either decrease or increase the rate of gene expression [ 17 , 18 ]. Epigenetic modification, including DNA methylation, has been observed in several human disease, including keloid scars [ 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…The aberrant addition (hypermethylation), or removal (hypomethylation) of the methyl group can either decrease or increase the rate of gene expression [ 17 , 18 ]. Epigenetic modification, including DNA methylation, has been observed in several human disease, including keloid scars [ 18 , 19 , 20 , 21 , 22 ]. These findings strongly suggested that DNA methylation is crucial in maintaining genome stability and plays an important role in disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Identification of Differentially Methylated CpG Sites in Fibroblasts from Keloid Scars

et al. 2020

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As a part of an abnormal healing process of dermal injuries and irritation, keloid scars arise on the skin as benign fibroproliferative tumors. Although the etiology of keloid scarring remains unsettled, considerable recent evidence suggested that keloidogenesis may be driven by epigenetic changes, particularly, DNA methylation. Therefore, genome-wide scanning of methylated cytosine-phosphoguanine (CpG) sites in extracted DNA from 12 keloid scar fibroblasts (KF) and 12 control skin fibroblasts (CF) (six normal skin fibroblasts and six normotrophic fibroblasts) was conducted using the Illumina Human Methylation 450K BeadChip in two replicates for each sample. Comparing KF and CF used a Linear Models for Microarray Data (Limma) model revealed 100,000 differentially methylated (DM) CpG sites, 20,695 of which were found to be hypomethylated and 79,305 were hypermethylated. The top DM CpG sites were associated with TNKS2, FAM45B, LOC723972, GAS7, RHBDD2 and CAMKK1. Subsequently, the most functionally enriched genes with the top 100 DM CpG sites were significantly (p ≤ 0.05) associated with SH2 domain binding, regulation of transcription, DNA-templated, nucleus, positive regulation of protein targeting to mitochondrion, nucleoplasm, Swr1 complex, histone exchange, and cellular response to organic substance. In addition, NLK, CAMKK1, LPAR2, CASP1, and NHS showed to be the most common regulators in the signaling network analysis. Taken together, these findings shed light on the methylation status of keloids that could be implicated in the underlying mechanism of keloid scars formation and remission.

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Biological significance of genome‐wide DNA methylation profiles in keloids

Abstract: NA Laryngoscope, 127:70-78, 2017.

Cited by 22 publications

References 43 publications

From genetics to epigenetics: new insights into keloid scarring

From genetics to epigenetics: new insights into keloid scarring

C1orf109L promote R-loop accumulation induced DNA damage to inhibit cell growth

Identification of Differentially Methylated CpG Sites in Fibroblasts from Keloid Scars

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