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JAMA Network Open Oct 2023Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and appears to have disproportionately higher incidence and worse outcomes among...
IMPORTANCE
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and appears to have disproportionately higher incidence and worse outcomes among younger African American females.
OBJECTIVE
To investigate whether epigenetic differences exist in TNBCs of younger African American females that may explain clinical disparities seen in this patient group.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study used clinical, demographic, DNA methylation (HumanMethylation450; Illumina), and gene expression (RNA sequencing) data for US patient populations from publicly available data repositories (The Cancer Genome Atlas [TCGA], 2006-2012, and Gene Expression Omnibus [GEO], 2004-2013) accessed on April 13, 2021. White and African American females with TNBC identified in TCGA (69 patients) and a validation cohort of 210 African American patients from GEO (GSE142102) were included. Patients without available race or age data were excluded. Data were analyzed from September 2022 through April 2023.
MAIN OUTCOMES AND MEASURES
DNA methylation and gene expression profiles of TNBC tumors by race (self-reported) and age were assessed. Age was considered a dichotomous variable using age 50 years as the cutoff (younger [<50 years] vs older [≥50 years]).
RESULTS
A total of 69 female patients (34 African American [49.3%] and 35 White [50.7%]; mean [SD; range] age, 55.7 [11.6; 29-82] years) with TNBC were included in the DNA methylation analysis; these patients and 210 patients in the validation cohort were included in the gene expression analysis (279 patients). There were 1115 differentially methylated sites among younger African American females. The DNA methylation landscape on TNBC tumors in this population had increased odds of enrichment of hormone (odds ratio [OR], 1.82; 95% CI, 1.21 to 2.67; P = .003), muscle (OR, 1.85; 95% CI, 1.44 to 2.36; P < .001), and proliferation (OR, 3.14; 95% CI, 2.71 to 3.64; P < .001) pathways vs other groups (older African American females and all White females). Alterations in regulators of these molecular features in TNBCs of younger African American females were identified involving hormone modulation (downregulation of androgen receptor: fold change [FC] = -2.93; 95% CI, -4.76 to -2.11; P < .001) and upregulation of estrogen-related receptor α (FC = 0.86; 95% CI, 0.34 to 1.38; P = .002), muscle metabolism (upregulation of FOXC1: FC = 1.33; 95% CI, 0.62 to 2.03; P < .001), and proliferation mediators (upregulation of NOTCH1: FC = 0.71; 95% CI, 0.23 to 1.19; P = .004 and MYC (FC = 0.81; 95% CI, 0.18 to 1.45; P = .01).
CONCLUSIONS AND RELEVANCE
These findings suggest that TNBC of younger African American females may represent a distinct epigenetic entity and offer novel insight into molecular alterations associated with TNBCs of this population. Understanding these epigenetic differences may lead to the development of more effective therapies for younger African American females, who have the highest incidence and worst outcomes from TNBC of any patient group.
Topics: Female; Humans; Middle Aged; Black or African American; Cross-Sectional Studies; Hormones; Triple Negative Breast Neoplasms; White; Epigenesis, Genetic; Adult; Aged; Aged, 80 and over
PubMed: 37796506
DOI: 10.1001/jamanetworkopen.2023.35821 -
Postepy Biochemii Jun 2023It has been known for years that diet impacts human health, including the risk of cancer development. Food components can both increase and reduce the risk of... (Review)
Review
It has been known for years that diet impacts human health, including the risk of cancer development. Food components can both increase and reduce the risk of carcinogenesis. Thereby, a wisely composed diet can extend life span and improve life quality. The favourable effect on health exert glucosinolates (GSLs), a group of secondary plant metabolites found in vegetables of the Brassicaceae family, such as broccoli, cauliflower, cabbage, and kohlrabi. Hydrolysis of GSLs results in the formation of compounds, like sulforaphane (SFN), phenylethyl isothiocyanate (PEITC) and 3,3′-Diindolylmethane (DIM), which are known for versatile anti-cancer activity. This review highlights advances on the role of the chosen GSLs on selected epigenetic mechanisms, i.e. DNA methylation, histone acetylation and microRNAs expression in cancer treatment.
Topics: Humans; Glucosinolates; Neoplasms; Brassica; Epigenesis, Genetic; DNA Methylation
PubMed: 37493557
DOI: 10.18388/pb.2023_478 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Nov 2023Methylation plays a vital role in biological systems. SAM (-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation... (Review)
Review
Methylation plays a vital role in biological systems. SAM (-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation reactions. SAM-dependent methyltransferases (MTase) transfer a methyl group from SAM to substrates, thereby altering their physicochemical properties or biological activities. In recent years, many SAM analogues with alternative methyl substituents have been synthesized and applied to methyltransferases that specifically transfer different groups to the substrates. These include functional groups for labeling experiments and novel alkyl modifications. This review summarizes the recent progress in the synthesis and application of SAM methyl analogues and prospects for future research directions in this field.
Topics: S-Adenosylmethionine; Methionine; Methyltransferases; Methylation; Racemethionine
PubMed: 38013176
DOI: 10.13345/j.cjb.230271 -
Nature Communications Dec 2023Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2...
Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.
Topics: Humans; Rats; Animals; Diabetes Mellitus, Type 2; Insulin Secretion; Insulin; DNA Methylation; Islets of Langerhans; Insulin-Secreting Cells; Transcription Factors; Epigenesis, Genetic; Mitochondria; Repressor Proteins; Forkhead Transcription Factors
PubMed: 38086799
DOI: 10.1038/s41467-023-43719-9 -
Epigenetics Dec 2023Occupational characteristics have been studied as risk factors for several age-related diseases and are thought to impact the ageing process, although there has been...
Occupational characteristics have been studied as risk factors for several age-related diseases and are thought to impact the ageing process, although there has been limited empirical work demonstrating an association between adverse occupational characteristics and accelerated ageing and this prior work has yielded mixed results. We used the 2010 and 2016 waves of the Health and Retirement Study ( = 1,251) to examine the association between occupation categories and self-reported working conditions of American adults at midlife and their subsequent epigenetic ageing as measured through five epigenetic clocks: PCHorvath, PCHannum, PCPhenoAge, PCGrimAge, and DunedinPACE. We found that individuals working in sales/clerical, service, and manual work show evidence of epigenetic age acceleration compared to those working in managerial/professional jobs and that the associations were stronger with second- and third-generation clocks. Individuals reporting high stress and high physical effort at work showed evidence of epigenetic age acceleration only on PCGrimAge and DunedinPACE. Most of these associations were attenuated after adjustment for race/ethnicity, educational attainment, and lifestyle-related risk factors. Sales/clerical work remained significantly associated with PCHorvath and PCHannum, while service work remained significantly associated with PCGrimAge. The results suggest that manual work and occupational physical activity may appear to be risk factors for epigenetic age acceleration through their associations with socioeconomic status, while stress at work may be a risk factor for epigenetic age acceleration through its associations with health behaviours outside of work. Additional work is needed to understand when in the life course and the specific mechanisms through which these associations occur.
Topics: Humans; United States; Aged; DNA Methylation; Aging; Ethnicity; Epigenesis, Genetic
PubMed: 37300823
DOI: 10.1080/15592294.2023.2218763 -
BMC Medical Genomics Sep 2023Cerebral ischaemia‒reperfusion (I/R) frequently causes late-onset neuronal damage. Breviscapine promotes autophagy in microvascular endothelial cells in I/R and can...
BACKGROUND
Cerebral ischaemia‒reperfusion (I/R) frequently causes late-onset neuronal damage. Breviscapine promotes autophagy in microvascular endothelial cells in I/R and can inhibit oxidative damage and apoptosis. However, the mediation mechanism of breviscapine on neuronal cell death is unclear.
METHODS
First, transcriptome sequencing was performed on three groups of mice: the neuronal normal group (Control group), the oxygen-glucose deprivation/ reoxygenation group (OGD/R group) and the breviscapine administration group (Therapy group). Differentially expressed genes (DEGs) between the OGD/R and control groups and between the Therapy and OGD/R groups were obtained by the limma package. N-methyladenosine (mA) methylation-related DEGs were selected by Pearson correlation analysis. Then, prediction and confirmation of drug targets were performed by Swiss Target Prediction and UniProt Knowledgebase (UniProtKB) database, and key genes were obtained by Pearson correlation analysis between mA-related DEGs and drug target genes. Next, gene set enrichment analysis (GSEA) and Ingenuity pathway analysis (IPA) were used to obtain the pathways of key genes. Finally, a circRNA-miRNA‒mRNA network was constructed based on the mRNAs, circRNAs and miRNAs.
RESULTS
A total of 2250 DEGs between the OGD/R and control groups and 757 DEGs between the Therapy and OGD/R groups were selected by differential analysis. A total of 7 mA-related DEGs, including Arl4d, Gm10653, Gm1113, Kcns3, Olfml2a, Stk26 and Tfcp2l1, were obtained by Pearson correlation analysis. Four key genes (Tfcp2l1, Kcns3, Olfml2a and Arl4d) were acquired, and GSEA showed that these key genes significantly participated in DNA repair, e2f targets and the g2m checkpoint. IPA revealed that Tfcp2l1 played a significant role in human embryonic stem cell pluripotency. The circRNA-miRNA‒mRNA network showed that mmu_circ_0001258 regulated Tfcp2l1 by mmu-miR-301b-3p.
CONCLUSIONS
In conclusion, four key genes, Tfcp2l1, Kcns3, Olfml2a and Arl4d, significantly associated with the treatment of OGD/R by breviscapine were identified, which provides a theoretical basis for clinical trials.
Topics: Humans; Animals; Mice; Methylation; Endothelial Cells; RNA, Circular; Cerebral Infarction; Computational Biology; MicroRNAs
PubMed: 37670341
DOI: 10.1186/s12920-023-01651-3 -
Cancer Metastasis Reviews Dec 2023Most of the cancer-associated mortality and morbidity can be attributed to metastasis. The role of epigenetic and epitranscriptomic alterations in cancer origin and... (Review)
Review
Most of the cancer-associated mortality and morbidity can be attributed to metastasis. The role of epigenetic and epitranscriptomic alterations in cancer origin and progression has been extensively demonstrated during the last years. Both regulations share similar mechanisms driven by DNA or RNA modifiers, namely writers, readers, and erasers; enzymes responsible of respectively introducing, recognizing, or removing the epigenetic or epitranscriptomic modifications. Epigenetic regulation is achieved by DNA methylation, histone modifications, non-coding RNAs, chromatin accessibility, and enhancer reprogramming. In parallel, regulation at RNA level, named epitranscriptomic, is driven by a wide diversity of chemical modifications in mostly all RNA molecules. These two-layer regulatory mechanisms are finely controlled in normal tissue, and dysregulations are associated with every hallmark of human cancer. In this review, we provide an overview of the current state of knowledge regarding epigenetic and epitranscriptomic alterations governing tumor metastasis, and compare pathways regulated at DNA or RNA levels to shed light on a possible epi-crosstalk in cancer metastasis. A deeper understanding on these mechanisms could have important clinical implications for the prevention of advanced malignancies and the management of the disseminated diseases. Additionally, as these epi-alterations can potentially be reversed by small molecules or inhibitors against epi-modifiers, novel therapeutic alternatives could be envisioned.
Topics: Humans; Epigenesis, Genetic; DNA Methylation; Neoplasms; RNA; DNA
PubMed: 37369946
DOI: 10.1007/s10555-023-10120-3 -
Epigenetics Dec 2024To explore the role of lncRNA mA methylation modification in aqueous humour (AH) of patients with pseudoexfoliation glaucoma (PXG). Patients with open-angle PXG under...
To explore the role of lncRNA mA methylation modification in aqueous humour (AH) of patients with pseudoexfoliation glaucoma (PXG). Patients with open-angle PXG under surgery from June 2021 to December 2021 were selected. Age- and gender-matched patients with age-related cataract (ARC) were chosen as control. Patients underwent detailed ophthalmic examinations. 0.05-0.1 ml AH were extracted during surgery for MeRIP-Seq and RNA-Seq. Joint analysis was used to screen lncRNAs with differential mA methylation modification and expression. Online software tools were used to draw lncRNA-miRNA-mRNA network (ceRNA). Expression of lncRNAs and mRNAs was confirmed using quantitative real-time PCR. A total of 4151 lncRNAs and 4386 associated mA methylation modified peaks were identified in the PXG group. Similarly, 2490 lncRNAs and 2595 associated mA methylation modified peaks were detected in the control. Compared to the ARC group, the PXG group had 234 hypermethylated and 402 hypomethylated mA peaks, with statistically significant differences (| Fold Change (FC) |≥2, < 0.05). Bioinformatic analysis revealed that these differentially methylated lncRNA enriched in extracellular matrix formation, tight adhesion, TGF- β signalling pathway, AMPK signalling pathway, and MAPK signalling pathway. Joint analysis identified 10 lncRNAs with differential mA methylation and expression simultaneously. Among them, the expression of ENST000000485383 and ROCK1 were confirmed downregulated in the PXG group by RT-qPCR. mA methylation modification may affect the expression of lncRNA and participate in the pathogenesis of PXG through the ceRNA network. ENST000000485383-hsa miR592-ROCK1 May be a potential target pathway for further investigation in PXG mA methylation.
Topics: Humans; RNA, Long Noncoding; Female; Exfoliation Syndrome; Male; Adenosine; Aged; Aqueous Humor; Gene Regulatory Networks; rho-Associated Kinases; Middle Aged; RNA, Messenger; DNA Methylation; Glaucoma, Open-Angle
PubMed: 38716769
DOI: 10.1080/15592294.2024.2348840 -
Neurology Dec 2023There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau...
BACKGROUND AND OBJECTIVES
There is an urgent need to identify novel noninvasive biomarkers for Alzheimer disease (AD) diagnosis. Recent advances in blood-based measurements of phosphorylated tau (pTau) species are promising but still insufficient to address clinical needs. Epigenetics has been shown to be helpful to better understand AD pathogenesis. Epigenetic biomarkers have been successfully implemented in other medical disciplines, such as oncology. The objective of this study was to explore the diagnostic accuracy of a blood-based DNA methylation marker panel as a noninvasive tool to identify patients with late-onset Alzheimer compared with age-matched controls.
METHODS
A case-control study was performed. Blood DNA methylation levels at 46 cytosine-guanine sites (21 genes selected after a comprehensive literature search) were measured by bisulfite pyrosequencing in patients with "probable AD dementia" following National Institute on Aging and the Alzheimer's Association guidelines (2011) and age-matched and sex-matched controls recruited at Neurology Department-University Hospital of Navarre, Spain, selected by convenience sampling. Plasma pTau181 levels were determined by Simoa technology. Multivariable logistic regression analysis was performed to explore the optimal model to discriminate patients with AD from controls. Furthermore, we performed a stratified analysis by sex.
RESULTS
The final study cohort consisted of 80 patients with AD (age: median [interquartile range] 79 [11] years; 58.8% female) and 100 cognitively healthy controls (age 77 [10] years; 58% female). A panel including DNA methylation levels at , , and genes and plasma pTau181 significantly improved (area under the receiver operating characteristic curve 0.93, 95% CI 0.89-0.97) the diagnostic performance of a single pTau181-based model, adjusted for age, sex, and ɛ4 genotype. The sensitivity and specificity of this panel were 83.30% and 90.00%, respectively. After sex-stratified analysis, DNA methylation levels showed consistent association with AD.
DISCUSSION
These results highlight the potential translational value of blood-based DNA methylation biomarkers for noninvasive diagnosis of AD.
REGISTRATION INFORMATION
Research Ethics Committee of the University Hospital of Navarre (PI17/02218).
Topics: Humans; Female; Aged; Male; Alzheimer Disease; DNA Methylation; Case-Control Studies; Biomarkers; Genotype; tau Proteins; Amyloid beta-Peptides
PubMed: 37827850
DOI: 10.1212/WNL.0000000000207865 -
BMC Biology Nov 2023The concept of the inheritance of acquired traits, a foundational principle of Lamarck's evolutionary theory, has garnered renewed attention in recent years. Evidence... (Review)
Review
BACKGROUND
The concept of the inheritance of acquired traits, a foundational principle of Lamarck's evolutionary theory, has garnered renewed attention in recent years. Evidence for this phenomenon remained limited for decades but gained prominence with the Överkalix cohort study in 2002. This study revealed a link between cardiovascular disease incidence and the food availability experienced by individuals' grandparents during their slow growth periods, reigniting interest in the inheritance of acquired traits, particularly in the context of non-communicable diseases. This scientometric analysis and systematic review comprehensively explores the current landscape of paternally transmitted acquired metabolic traits.
RESULTS
Utilizing Scopus Advanced search and meticulous screening, we included mammalian studies that document the inheritance or modification of metabolic traits in subsequent generations of unexposed descendants. Our inclusive criteria encompass intergenerational and transgenerational studies, as well as multigenerational exposures. Predominantly, this field has been driven by a select group of researchers, potentially shaping the design and focus of existing studies. Consequently, the literature primarily comprises transgenerational rodent investigations into the effects of ancestral exposure to environmental pollutants on sperm DNA methylation. The complexity and volume of data often lead to multiple or redundant publications. This practice, while understandable, may obscure the true extent of the impact of ancestral exposures on the health of non-exposed descendants. In addition to DNA methylation, studies have illuminated the role of sperm RNAs and histone marks in paternally acquired metabolic disorders, expanding our understanding of the mechanisms underlying epigenetic inheritance.
CONCLUSIONS
This review serves as a comprehensive resource, shedding light on the current state of research in this critical area of science, and underscores the need for continued exploration to uncover the full spectrum of paternally mediated metabolic inheritance.
Topics: Humans; Animals; Male; Epigenesis, Genetic; Paternal Inheritance; Cohort Studies; Semen; DNA Methylation; Mammals
PubMed: 37953286
DOI: 10.1186/s12915-023-01744-6