Epigenomics最新文献

Introduction: Neuroblastoma, a highly aggressive pediatric cancer, presents significant treatment challenges due to its rapid proliferation, and resistance to conventional therapies. Growing evidence emphasizes the critical role of epigenetic modifications in tumor progression.

Research design and methods: In this study, we explored the therapeutic potential of the MDM2 inhibitor RG-7388 alongside the DNMT inhibitors CM-272 and SGI-1027 in SK-N-SH and IMR-32 neuroblastoma cells. We hypothesized that RG-7388, CM-272, and SGI-1027 would induce p21 upregulation, leading to cell cycle arrest and activation of cell death pathways.

Results: Cells treated with the above listed drug exhibited significant cell death, as determined by cell viability and caspase-3/7 activation assays. qRT-PCR and Western blot analyses revealed increased expression of p21 and pro-apoptotic BAX, along with decreased levels of the anti-apoptotic protein BCL-XL. Notably, RG-7388 treatment induced substantial PARP cleavage, consistent with activation of apoptosis.These findings suggest that MDM2 and DNMT1 inhibition promotes apoptosis through a p21-driven mechanism. Importantly, DNMT1 inhibition could provide a therapeutic alternative for neuroblastomas with p53 mutations, where p53 dependent mechanism is ineffective.

Conclusion: Our results suggest that, if validated further, RG-7388, CM-272, and SGI-1027 could become effective therapeutic agents for treating aggressive neuroblastoma that may become resistant to first or second line of treatment.

Background: Previous studies reported that altered mitochondrial methylation in Alzheimer's disease (AD), however, whether epigenetic modifications in mitochondrial genomes contribute to preclinical AD remains unclear. This study aimed to investigate mitochondrial methylation changes in individuals with cognitive decline.

Research design and methods: We examined whole mitochondrial genome methylation in 50 individuals with mild cognitive impairment (MCI) and 50 individuals without MCI, using bisulfite amplicon sequencing, assessing methylation at 366 Cytosine-guanine oligodeoxynucleotide (CpG) sites.

Results: We found the overall methylation level of mitochondrial DNA (mtDNA) in each subject was relatively low, ranging from 0% to 15%. Global methylation was significantly higher in individuals with cognitive decline compared to controls (3.86% vs. 3.46%, p = 0.037), with 34 differentially methylated CpG sites identified. Methylation differences (MD) between cognitive decline individuals and controls were 22.93 ± 5.60% at chrM6465 (Q = 0.013), 12.55 ± 3.02% at chrM9612 (Q = 0.013), 11.45 ± 3.88% at chrM11762 (Q = 0.159) and 11.03 ± 3.88% at chrM11766 (Q = 0.172), respectively, while the level of MD at chrM15812 was -13.11 ± 4.31% (Q = 0.159) after Benjamini-Hochberg FDR adjusted. Furthermore, Methylation at specific sites were significantly correlated with Mini-Mental State Examination scores, distinguishing individuals with cognitive decline from controls.

Conclusions: Our study provides an mtDNA methylation map and suggests a role for these sites in preclinical AD pathogenesis.

Background: In elderly patients, bone regeneration is impeded by age-related shifts in mesenchymal stem cell differentiation propensity toward adipogenesis over osteogenesis. We investigated whether DNA demethylation by 5‑aza‑2'‑deoxycytidine (5azaC) synergizes with Wnt Family Member 3A (Wnt3a) signaling to induce osteogenic potential in 3T3‑L1 pre-adipocytes, generating osteoblast-like cells.

Methods: 3T3‑L1 pre-adipocytes were treated with 5azaC and/or Wnt3a. Osteogenic differentiation was assessed via ALP activity, mineralization assays, and marker expression. Transcriptomic and epigenomic profiling were performed and compared with MC3T3-E1 cells. Functional relevance of candidate genes was examined using siRNA knockdown.

Results: Transcriptomic and epigenomic profiling revealed that 5azaC and Wnt3a co-treatment induced broader gene expression and methylation changes than either treatment alone, closely resembling the osteogenic profile of MC3T3-E1 pre-osteoblasts. Among the overlapping differentially methylated and steadily expressed genes, Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Eta (Ywhah) and Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Epsilon (Ywhae) emerged as key regulators, whose knockdown notably enhanced Alpl expression even without 5azaC.

Conclusions: Combining 5azaC-induced demethylation with Wnt3a is a potent strategy to redirect pre-adipocytes toward osteogenesis. Identification of key targets like Ywhah and Ywhae provides mechanistic insight into trans-differentiation and suggests therapeutic potential for bone regeneration, particularly in elderly periodontal patients.

Aim: This study compared methylation-specific quantitative melt analysis of FMR1 and SNRPN methylation (mDNA) using automated bisulfite conversion by the magnetic-bead-based IsoPure and column-based QIAcube HT systems.

Methods: Two bisulfite conversion methods were assessed on 3.2 mm punches from the same archival blood spots stored at room temperature for >10 years of individuals with FMR1 premutation (n = 20), fragile X syndrome (FXS, n = 20), or chromosome 15 imprinting disorders (n = 50) and freshly made blood spots from 184 newborns from the general population. Performance criteria were: (i) diagnostic sensitivity and specificity for the conditions screened; (ii) reaction failure rate; (iii) variability in mDNA between groups.

Results: Both methods showed 100% sensitivity and specificity for differentiating FXS and individual chromosome 15 imprinting disorders. IsoPure showed reaction failure rates of 0.365% for SNRPN and 0.74% for FMR1 compared to 19.34% and 2.56%, for QIAcube HT, respectively, with most failed reactions originating from archival blood spots. IsoPure showed lower variability in mDNA values in the neurotypical and condition-specific ranges.

Conclusion: The IsoPure system showed superior performance especially on archival samples, with broader applications for screening and diagnostic testing requiring high-throughput mDNA analyses on materials of limited quantity and quality.

The placenta is a dynamic organ that serves numerous purposes for fostering a successful pregnancy and the delivery of a healthy infant in humans. It performs critical functions in nutrient and oxygen transport, immune modulation, and hormonal regulation. DNA methylation, a key epigenetic mechanism of transcriptional regulation, plays a key role in the underlying etiologies of placenta-related health complications. Therefore, assessing placental DNA methylation is essential for understanding how adverse prenatal exposures may impact both short-term and long-term health outcomes in women and children. In this review, we summarize current knowledge on the effects of prenatal exposures on placental DNA methylation and their implications for maternal and child health, focused on human population studies. We also outline five critical directions for human placental DNA methylation research: (1) Investigating sex-specific DNA methylation patterns, (2) Assessing cell type-specific DNA methylation signatures, (3) Applying causal inference methods, (4) Integrating multi-omics approaches, and (5) Using DNA methylation as a biomarker for environmental exposures and developmental outcomes. Advancing research in these areas will enhance our understanding of the biological underpinnings of the developmental origins of health and disease (DOHaD) hypothesis and maximize the potential of placental samples to inform DOHaD-related research.

Background: Hispanics/Latinos in the United States experience disproportionately high psychosocial factors compared to non-Hispanic/Latino Whites. Psychosocial factors may accelerate biological aging, measured by epigenetic age acceleration (EAA), a DNA methylation biomarker predictive of morbidity and mortality.

Methods: We investigated the cumulative impact of psychosocial factors on EAA over time in 922 adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Psychosocial exposure profiles were derived using self-organizing maps (SOM), an unsupervised clustering method. We calculated EAA from whole blood DNA methylation at two timepoints using GrimAge and DunedinPACE.

Results: SOM identified four clusters: Cluster 1 (n = 196; 21.3%) had high levels of all psychosocial factors; Cluster 2 (n = 250; 27.1%) exhibited chronic, traumatic, and childhood stress; Cluster 3 (n = 250; 27.1%) showed mental health symptoms, low social support, and high perceived stress; and Cluster 4 (n = 238; 24.5%) had relatively low psychosocial stress. Adjusted weighted linear mixed models exhibited increased GrimAge in Cluster 1 (1.27 years, 95% CI: 0.57,1.97) and Cluster 2 (0.62 years, 95% CI: 0.01,1.23) compared to Cluster 4. DunedinPACE increased 3% (95% CI: 0.01,0.05) and 2% (95% CI: 0.001,0.04) in Clusters 1 and 3, respectively.

Conclusions: These findings highlight the cumulative impact of psychosocial factors on EAA and how stressors can get "under the skin" and contribute to health disparities.

Background: Approximately one-third of breast cancer (BC) patients show poorer cognitive function (CF). Using DNA methylation (DNAm) data, here we aimed to identify genes and biological pathways associated with CF in postmenopausal women with early-stage hormone receptor-positive (HR+) BC.

Methods: Epigenome-wide association studies (EWAS) and differentially methylated region analyses were performed for each CF phenotype (seven objective domains and one subjective phenotype) using DNAm data from whole blood samples (n = 109) taken at the time of enrollment.

Results: When adjusting for age, verbal IQ scores, and global DNAm signature, cg10331779 near CTNND2 (p-value = $9.65\times {10}^{-9}$) and cg25906741 in MLIP (p-value = $2.01\times {10}^{-8}$) were associated with processing speed and subjective CF, respectively, while regions in/near SLC6A11, PRKG1/CSTF2T, and FAM3B for processing speed, and regions in/near PI4KB and SGCE/PEG10 for mental flexibility were differentially methylated. In addition, beta-estradiol was identified as a common upstream regulator for all the CF phenotypes, suggesting an essential role of estrogen in explaining variation in CF of HR+ BC patients.

Conclusions: In our EWAS of 8 CF phenotypes, we found two epigenome-wide significant signals, one for processing speed and the other for subjective CF. We also found three differentially methylated regions associated with processing speed and two associated with mental flexibility.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT02793921.

In this perspective, Akhtar et al provide a brief overview of Enhancer of Zeste Homolog 2 (EZH2) and SET and MYND-domain containing 3 (SMYD3) as histone methyltransferases that function both as activators and repressors of gene transcription in cancer. The importance of deciphering the mechanisms underlying this bifaceted function toward thoughtful pharmacologic interventions is underlined and protein or mRNA degradation are highlighted as the most biologically rational pharmaceutical platforms to target these bifaceted histone methyltransferases.

Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics - provides a comprehensive framework to study aging as an interconnected network. In this Perspective, I explore how multiomic strategies, particularly those leveraging epigenomic and single-cell data, are reshaping our understanding of aging biology. Epigenetic alterations, including DNA methylation and histone modifications, are not only hallmarks but also powerful biomarkers of biological age. I discuss advances in multiomic aging clocks, cross-tissue atlases, and single-cell spatial technologies that decode aging at unprecedented resolution. I also build on a prior review I wrote with colleagues, Epigenomics. 2023;15(14):741-754, which introduced the concept of pathological epigenetic events that are reversible (PEERs) - epigenetic alterations linked to early-life exposures that predispose to aging and disease but may be therapeutically modifiable. This Perspective examines how PEERs and multiomics intersect to inform biomarkers, geroprotective interventions, and personalized aging medicine. Finally, I highlight integration challenges, ethical concerns, and the need for standardization to accelerate clinical translation. Together, these insights position multiomics as a central pillar in the future of aging research.

Background: Junctional adhesion molecule 3 (JAM3) is frequently epigenetically silenced in various cancers, but its role in serous ovarian carcinoma (SOC) was unclear.

Research design and methods: This study evaluated JAM3 expression and methylation in SOC using immunohistochemistry (IHC), bisulfite sequencing PCR (BSP), and quantitative methylation-specific PCR (qMSP). Cell proliferation, apoptosis, migration, and invasion were examined using CCK8, flow cytometry, scratch-wound, and transwell assays. Pathways downstream of JAM3 were explored through RNA sequencing (RNA-seq) and Western Blot analysis, with rescue experiments using AKT inhibitor (MK2206) to validate pathway dependency.

Results: Findings revealed that JAM3 expression is significantly reduced in SOC, correlating with advanced clinical stages and poor prognosis. Methylation levels of the JAM3 promoter were higher in SOC samples compared to normal tissues and were linked to increased Ki67 expression and clinical stages. Functionally, overexpressing JAM3 in SOC cells triggered apoptosis and hindered proliferation, migration, and invasion, whereas JAM3 knockdown produced opposite effects. Mechanism analysis demonstrated that JAM3 affects SOC cell proliferation through the PI3K/AKT signaling pathway.

Conclusions: Conclusively, JAM3 acts as a tumor suppressor in SOC by modulating the PI3K/AKT pathway. These insights present JAM3 as a promising therapeutic target for SOC diagnosis and treatment.