An epigenetic mechanism underlying chromosome 17p deletion-driven tumorigenesis

DNA hypermethylation is an important epigenetic mechanism for gene expression inactivation in head and neck cancer (HNC). Saliva has emerged as a novel liquid biopsy representing a potential source of biomarkers. We performed a comprehensive meta-analysis to evaluate the overall diagnostic accuracy of salivary DNA methylation for detecting HNC. PubMed EMBASE, Web of Science, LILACS, and the Cochrane Library were searched. Study quality was assessed by the Quality Assessment for Studies of Diagnostic Accuracy-2, and sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (dOR), and their corresponding 95% confidence intervals (CIs) were calculated using a bivariate random-effect meta-analysis model. Meta-regression and subgroup analyses were performed to assess heterogeneity. Eighty-four study units from 18 articles with 8368 subjects were included. The pooled sensitivity and specificity of salivary DNA methylation were 0.39 and 0.87, respectively, while PLR and NLR were 3.68 and 0.63, respectively. The overall area under the curve (AUC) was 0.81 and the dOR was 8.34. The combination of methylated genes showed higher diagnostic accuracy (AUC, 0.92 and dOR, 36.97) than individual gene analysis (AUC, 0.77 and dOR, 6.02). These findings provide evidence regarding the potential clinical application of salivary DNA methylation for HNC diagnosis.

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Distinct Ring1b complexes defined by DEAD-box helicases and EMT transcription factors synergistically enhance E-cadherin silencing in breast cancer

Cell Death and Disease ◽

10.1038/s41419-021-03491-4 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Yawei Wang ◽

Yingying Sun ◽

Chao Shang ◽

Lili Chen ◽

Hongyu Chen ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factors ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Epigenetic Mechanism ◽

Regulation Mechanism ◽

Rna Helicases ◽

Mesenchymal Transition ◽

Dead Box ◽

E Cadherin

AbstractRing1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell–cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

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Polyphenol-Enriched Blueberry Preparation Controls Breast Cancer Stem Cells by Targeting FOXO1 and miR-145

Molecules ◽

10.3390/molecules26144330 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4330

Author(s):

Jean-François Mallet ◽

Roghayeh Shahbazi ◽

Nawal Alsadi ◽

Chantal Matar

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Mirna Expression ◽

Epigenetic Mechanism ◽

Breast Cancer Cell Lines ◽

Relative Expression ◽

Target Proteins ◽

Pathological Characteristics

Scientific evidence supports the early deregulation of epigenetic profiles during breast carcinogenesis. Research shows that cellular transformation, carcinogenesis, and stemness maintenance are regulated by epigenetic-specific changes that involve microRNAs (miRNAs). Dietary bioactive compounds such as blueberry polyphenols may modulate susceptibility to breast cancer by the modulation of CSC survival and self-renewal pathways through the epigenetic mechanism, including the regulation of miRNA expression. Therefore, the current study aimed to assay the effect of polyphenol enriched blueberry preparation (PEBP) or non-fermented blueberry juice (NBJ) on the modulation of miRNA signature and the target proteins associated with different clinical-pathological characteristics of breast cancer such as stemness, invasion, and chemoresistance using breast cancer cell lines. To this end, 4T1 and MB-MDM-231 cell lines were exposed to NBJ or PEBP for 24 h. miRNA profiling was performed in breast cancer cell cultures, and RT-qPCR was undertaken to assay the expression of target miRNA. The expression of target proteins was examined by Western blotting. Profiling of miRNA revealed that several miRNAs associated with different clinical-pathological characteristics were differentially expressed in cells treated with PEBP. The validation study showed significant downregulation of oncogenic miR-210 expression in both 4T1 and MDA-MB-231 cells exposed to PEBP. In addition, expression of tumor suppressor miR-145 was significantly increased in both cell lines treated with PEBP. Western blot analysis showed a significant increase in the relative expression of FOXO1 in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Furthermore, a significant decrease was observed in the relative expression of N-RAS in 4T1 and MDA-MB-231 cells exposed to PEBP and in MDA-MB-231 cells exposed to NBJ. Our data indicate a potential chemoprevention role of PEBP through the modulation of miRNA expression, particularly miR-210 and miR-145, and protection against breast cancer development and progression. Thus, PEBP may represent a source for novel chemopreventative agents against breast cancer.

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Childhood Obesity-Related Mechanisms: MicroRNome and Transcriptome Changes in a Nested Case-Control Study

Biomedicines ◽

10.3390/biomedicines9080878 ◽

2021 ◽

Vol 9 (8) ◽

pp. 878

Author(s):

Jin Hee Kim ◽

Da Hae Kim ◽

Youn-Hee Lim ◽

Choong Ho Shin ◽

Young Ah Lee ◽

...

Keyword(s):

Childhood Obesity ◽

Epigenetic Mechanism ◽

Akt Signaling Pathway ◽

Normal Children ◽

Protein Levels ◽

Adverse Health Outcomes ◽

Genome Wide ◽

Nested Case Control ◽

Genome Wide Expression ◽

Control Study

Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases.

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Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children

Psychological Medicine ◽

10.1017/s0033291720004353 ◽

2020 ◽

pp. 1-11

Author(s):

Lorenza Dall’ Aglio ◽

Jolien Rijlaarsdam ◽

Rosa H. Mulder ◽

Alexander Neumann ◽

Janine F. Felix ◽

...

Keyword(s):

Dna Methylation ◽

Stress Responses ◽

Association Studies ◽

Maternal Sensitivity ◽

Population Based ◽

Epigenetic Mechanism ◽

Developmental Problems ◽

Maternal Caregiving ◽

Typical Variation

Abstract Background Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Methods Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Results Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10−07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. Conclusions These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

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ChIP-seq Profiling Identifies Histone Deacetylase 2 Targeting Genes Involved in Immune and Inflammatory Regulation Induced by Calcitonin Gene-Related Peptide in Microglial Cells

Journal of Immunology Research ◽

10.1155/2020/4384696 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Xingjing Guo ◽

Dan Chen ◽

Shuhong An ◽

Zhaojin Wang

Keyword(s):

Signaling Pathway ◽

Histone Deacetylase ◽

Calcitonin Gene Related Peptide ◽

Epigenetic Mechanism ◽

Microglial Cells ◽

Transcriptional Level ◽

Gene Promoters ◽

Histone Deacetylase 2 ◽

Related Peptide ◽

Calcitonin Gene

Calcitonin gene-related peptide (CGRP) is a mediator of microglial activation at the transcriptional level. The involvement of the epigenetic mechanism in this process is largely undefined. Histone deacetylase (HDAC)1/2 are considered important epigenetic regulators of gene expression in activated microglia. In this study, we examined the effect of CGRP on HDAC2-mediated gene transcription in microglial cells through the chromatin immunoprecipitation sequencing (ChIP-seq) method. Immunofluorescence analysis showed that mouse microglial cells (BV2) expressed CGRP receptor components. Treatment of microglia with CGRP increased HDAC2 protein expression. ChIP-seq data indicated that CGRP remarkably altered promoter enrichments of HDAC2 in microglial cells. We identified 1271 gene promoters, whose HDAC2 enrichments are significantly altered in microglia after CGRP treatment, including 1181 upregulating genes and 90 downregulating genes. Bioinformatics analyses showed that HDAC2-enriched genes were mainly associated with immune- and inflammation-related pathways, such as nitric oxide synthase (NOS) biosynthetic process, retinoic acid-inducible gene- (RIG-) like receptor signaling pathway, and nuclear factor kappa B (NF-κB) signaling pathway. The expression of these key pathways (NOS, RIG-I, and NF-κB) were further verified by Western blot. Taken together, our findings suggest that genes with differential HDAC2 enrichments induced by CGRP function in diverse cellular pathways and many are involved in immune and inflammatory responses.

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Detection of differentially methylated CpG sites between tumor samples with uneven tumor purities

Bioinformatics ◽

10.1093/bioinformatics/btz885 ◽

2019 ◽

Vol 36 (7) ◽

pp. 2017-2024

Author(s):

Weiwei Zhang ◽

Ziyi Li ◽

Nana Wei ◽

Hua-Jun Wu ◽

Xiaoqi Zheng

Keyword(s):

Real Data ◽

R Package ◽

Differential Methylation ◽

Least Square ◽

Epigenetic Mechanism ◽

Supplementary Information ◽

Cpg Sites ◽

Tumor Purity ◽

Different Sources ◽

Normal Controls

Abstract Motivation Inference of differentially methylated (DM) CpG sites between two groups of tumor samples with different geno- or pheno-types is a critical step to uncover the epigenetic mechanism of tumorigenesis, and identify biomarkers for cancer subtyping. However, as a major source of confounding factor, uneven distributions of tumor purity between two groups of tumor samples will lead to biased discovery of DM sites if not properly accounted for. Results We here propose InfiniumDM, a generalized least square model to adjust tumor purity effect for differential methylation analysis. Our method is applicable to a variety of experimental designs including with or without normal controls, different sources of normal tissue contaminations. We compared our method with conventional methods including minfi, limma and limma corrected by tumor purity using simulated datasets. Our method shows significantly better performance at different levels of differential methylation thresholds, sample sizes, mean purity deviations and so on. We also applied the proposed method to breast cancer samples from TCGA database to further evaluate its performance. Overall, both simulation and real data analyses demonstrate favorable performance over existing methods serving similar purpose. Availability and implementation InfiniumDM is a part of R package InfiniumPurify, which is freely available from GitHub (https://github.com/Xiaoqizheng/InfiniumPurify). Supplementary information Supplementary data are available at Bioinformatics online.

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