DNA Methylation Research Articles

Aberrant promoter methylation of CTHRC1 gene and its clinicopathological characteristics in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is genetically complex and difficult to treat. Detection in the early stage is challenging, leading to diagnosis at advanced stages with limited treatment options. This study examined the collagen triple helix repeat containing 1 gene (CTHRC1) as a potential biomarker and therapeutic target in HNSCC. Despite documented CTHRC1 upregulation in various cancers, the underlying causes remain unclear. The objective was to investigate potential epigenetic regulation of CTHRC1 expression through the analysis of promoter methylation. CTHRC1 DNA methylation, mRNA, and its protein expression were analysed using The Cancer Genome Atlas (TCGA) HNSCC cohort and oral squamous cell carcinoma (OSCC) patient samples. Functional analysis included scrutinizing the protein-protein interaction network and associations with DisGeNET (disease gene network). Various statistical methods were employed for analysis. HNSCC tumours exhibited significant hypomethylation of CTHRC1 DNA, correlating with advanced disease features. Elevated mRNA and protein expression of CTHRC1 further support its role in disease progression. High CTHRC1 gene expression was associated with a poorer prognosis. The protein interaction network implicated crucial pathways in cancer development and links to oral submucous fibrosis. Despite the limitations of this study, including the use of retrospective data and need for functional experiments, CTHRC1 shows potential as a prognostic predictor and target for therapeutic applications in HNSCC, paving the way for further research and improved patient management.

Human health risk assessment by exposure to contaminants from an urban reservoir: a pilot study in the Madin Dam (México).

Water contamination greatly impacts human health. The Metropolitan Area of the Valley of Mexico (MAVM) is one of the most densely inhabited and polluted places globally, with a significant problem being the rising water demand. The research aims to assess the impact of metals such as iron, aluminum, lead, cadmium, and total chromium, among others, in the water of the Madin Dam, a key reservoir in the area's water supply. The assessment concentrated on individuals who were in good health and had been exposed to these pollutants. It analyzed factors such as levels of oxidized proteins; changes in the function of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase); and their genetic expression, the occurrence of micronuclei, and the amount of DNA methylation. The findings were linked to the metals present in the MAVM drinking water, and the risk was evaluated. The research included four groups: two associated with the Madin Dam, consisting of persons living nearby or using water from the reservoir, and two acting as a control. The study highlighted a significant link between long-term exposure to pollutants in drinking water and elevated levels of oxidized proteins, increased micronuclei frequency, changes in antioxidant enzyme activity and gene expression, and a higher percentage of 5-methylcytosine. The risk assessment showed that people who use drinking water and/or consume fish from Madin Dam have a potential higher risk associated with metal contamination.

High-Grade Astrocytoma With Piloid Features.

High-grade astrocytoma with piloid features (HGAP) is a newly recognized glioma defined by its methylation profile. Understanding of its clinical, histologic, and molecular characteristics continues to evolve. To review the HGAP literature, emphasizing updates in our understanding of the entity since its codification in the 2021 World Health Organization (WHO) Blue Book. Additionally, to present a case series illustrating a single institutional experience with HGAP. The English-language HGAP literature from 2018 to 2024 was reviewed. Four cases of HGAP were reviewed, along with relevant medical records. HGAP is an important consideration in the differential diagnosis of isocitrate dehydrogenase-wild-type gliomas and is more frequently encountered in adults. A handful of studies published following the entity's codification in the 2021 WHO Blue Book have refined our understanding of its clinical, histologic, and hallmark molecular characteristics. The most substantial updates include the description of 3 provisional subtypes, further characterization of an association with neurofibromatosis 1 syndrome, identification of new rare molecular alterations, and documentation of a unique case of possible transformation of pilocytic astrocytoma into HGAP. Clues to the diagnosis of HGAP include histologic infiltrating glioma with moderate pleomorphism, posterior fossa location, CDKN2A/B (cyclin dependent kinase inhibitor 2A/B) deletion, MAPK (mitogen-activated protein kinase) pathway alterations, ATRX (alpha thalassemia/mental retardation syndrome X-linked) loss, and association with neurofibromatosis 1 syndrome in some cases; these findings should prompt further molecular testing, including genome-wide DNA methylation analysis, which is currently essential for diagnosis.

Whole Blood DNA Methylation Analysis Reveals Epigenetic Changes Associated with ARSACS

Whole Blood DNA Methylation Analysis Reveals Epigenetic Changes Associated with ARSACS

Classification of Fibro-osseous Tumors in the Craniofacial Bones using DNA Methylation and Copy Number Alterations.

Fibro-osseous tumors of the craniofacial bones are a heterogeneous group of lesions comprising cemento-osseous dysplasia (COD), cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF), psammomatoid ossifying fibroma (PsOF), fibrous dysplasia (FD), and low-grade osteosarcoma (LGOS) with overlapping clinicopathological features. However, their clinical behavior and treatment differ significantly, underlining the need for accurate diagnosis. Molecular diagnostic markers exist for subsets of these tumors, including GNAS mutations in FD, SATB2 fusions in PsOF, mutations involving the RAS-MAPK signaling pathway in COD, and MDM2 amplification in LGOS. Since DNA methylation and copy number profiling are well established for the classification of central nervous system tumors, our aim was to investigate whether this tool might be used as well for classifying fibro-osseous tumors in the craniofacial bones. We collected a well-characterized, multicenter cohort with available molecular data, including COD (n = 20), COF (n = 13), JTOF (n = 10), PsOF (n = 25), FD (n = 23), LGOS (n = 4), and high-grade osteosarcoma (HGOS; n = 11). Genome-wide DNA methylation and copy number variation data were generated using the Illumina Infinium Methylation EPIC array interrogating >850 000 CpG sites. DNA methylation profiling yielded evaluable results in 73/106 tumors, including 6 CODs, 12 COFs, 6 JTOFs, 19 PsOFs, 18 FDs, 2 LGOSs, and 10 HGOSs. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that FD, extragnatic PsOF, and HGOS formed distinct clusters. Surprisingly, COD, COF, JTOF, and mandibular PsOF clustered together, apart from other craniofacial bone tumors. LGOS did not form a distinct cluster, likely due to the low number of cases. Copy number analysis revealed that FD, COD, COF, JTOF, and PsOF were typically characterized by flat copy number profiles compared to LGOS with gains of chromosome 12 and HGOS with multiple heterogeneous copy number alterations. In conclusion, using DNA methylation and copy number profiles, benign fibro-osseous tumors can be separated from low-grade and high-grade osteosarcomas in the craniofacial bones, which is of diagnostic value in challenging cases with overlapping clinicopathological features.

The strigolactones-mediated DNA demethylation activates the phosphoinositide pathway in response to salt stress.

Salt stress severely affects the growth and development of tomato. Strigolactones (SLs) and DNA methylation have been shown to be involved in the growth and development and response to salt stress in tomato. However, the regulation of SLs on DNA methylation in tomato under salt stress remains unclear. In this study, the interaction between SLs and DNA methylation inhibitors 5-azacytidine (5-azaC) alleviate salt stress damage by increasing the plant height, stem diameter, leaf area, and root length of tomato, as well as enhancing the biosynthesis of chlorophyll, carotenoid and flavonoid. The transcriptome and genome-wide methylation analysis between NaCl and NaCl + GR24 treatment show that plant-pathogen interaction, MAPK signaling pathway, plant hormone signal transduction and phosphatidylinositol signaling system may be means for SLs in response to salt stress. Among, SLs strikingly up-regulate the pivotal genes related to phosphatidylinositol signaling system, and reduce CHG methylation level in promoter and body region of these genes under salt stress, implying that SLs mediated-demethylation may promote gene expression. The determination results of relevant metabolites and gene expression levels in the phosphatidylinositol signaling system suggest that PIP2, DAG, IP3, and PA are raised by co-treatment of SLs and 5-azaC under salt stress relative to NaCl + 5-azaC treatment. The same response pattern is also presented in the SlPLC2, SlNPC1, SlPLD-Z, SlPLD-B, SlDGK1, SlDGK5, SlDGK7 and SlPIP5K9 genes. These results strongly indicate that phosphatidylinositol signaling system response to salt stress is related to the SLs mediated-demethylation, and provide a potential means for defenses salt stress in tomato.

Placental PFAS concentrations are associated with perturbations of placental DNA methylation.

The placenta is crucial for fetal development, is affected by PFAS toxicity, and evidence is accumulating that gestational PFAS perturb the epigenetic activity of the placenta. Gestational PFAS exposure can adversely affect offspring, yet individual and cumulative impacts of PFAS on the placental epigenome remain underexplored. Here, we conducted an epigenome-wide association study (EWAS) to examine the relationships between placental PFAS levels and DNA methylation in a cohort of mother-infant dyads in Arkansas (N=151). We measured 17 PFAS in human placental tissues and quantified placental DNA methylation levels via the Illumina EPIC Microarray. We tested for differential DNA methylation with individual PFAS, and with mixtures of multiple PFAS. Our results demonstrated that numerous epigenetic loci were perturbed by PFAS, with PFHxS exhibiting the most abundant effects. Mixture analyses suggested cumulative effects of PFOA and PFOS, while PFHxS may act more independently. We additionally explored whether sex-specific effects may be present and concluded that future large studies should explicitly test for sex-specific effects. The genes that are annotated to our PFAS-associated epigenetic loci are primarily involved in growth processes and cardiometabolic health, while some genes are involved in neurodevelopment. These findings shed light on how prenatal PFAS exposures affect birth outcomes and children's health, emphasizing the importance of understanding PFAS mechanisms in the in-utero environment.

Leveraging Epigenetic Alterations in Pancreatic Ductal Adenocarcinoma for Clinical Applications.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by late detection and poor prognosis. Recent research highlights the pivotal role of epigenetic alter- ations in driving PDAC development and progression. These changes, in conjunction with genetic mutations, contribute to the intricate molecular landscape of the disease. Specific modifications in DNA methylation, histone marks, and non-coding RNAs are emerging as robust predictors of disease progression and patient survival, offering the potential for more precise prognostic tools compared to conventional clinical staging. Moreover, the detection of epigenetic alterations in blood and other non-invasive samples holds promise for earlier diagnosis and improved manage- ment of PDAC. This review comprehensively summarises current epigenetic research in PDAC and identifies persisting challenges. These include the complex nature of epigenetic profiles, tumour hetero- geneity, limited access to early-stage samples, and the need for highly sensitive liquid biopsy technologies. Addressing these challenges requires the standardisation of methodologies, integra- tion of multi-omics data, and leveraging advanced computational tools such as machine learning and artificial intelligence. While resource-intensive, these efforts are essential for unravelling the functional consequences of epigenetic changes and translating this knowledge into clinical appli- cations. By overcoming these hurdles, epigenetic research has the potential to revolutionise the management of PDAC and improve patient outcomes.

Epigenomics-guided precision oncology: Chromatin variants in prostate tumor evolution.

Prostate cancer is a common malignancy that in 5%-30% leads to treatment-resistant and highly aggressive disease. Metastasis-potential and treatment-resistance is thought to rely on increased plasticity of the cancer cells-a mechanism whereby cancer cells alter their identity to adapt to changing environments or therapeutic pressures to create cellular heterogeneity. To understand the molecular basis of this plasticity, genomic studies have uncovered genetic variants to capture clonal heterogeneity of primary tumors and metastases. As cellular plasticity is largely driven by non-genetic events, complementary studies in cancer epigenomics are now being conducted to identify chromatin variants. These variants, defined as genomic loci in cancer cells that show changes in chromatin state due to the loss or gain of epigenomic marks, inclusive of histone post-translational modifications, DNA methylation and histone variants, are considered the fundamental units of epigenomic heterogeneity. In prostate cancer chromatin variants hold the promise of guiding the new era of precision oncology. In this review, we explore the role of epigenomic heterogeneity in prostate cancer, focusing on how chromatin variants contribute to tumor evolution and therapy resistance. We therefore discuss their impact on cellular plasticity and stochastic events, highlighting the value of single-cell sequencing and liquid biopsy epigenomic assays to uncover new therapeutic targets and biomarkers. Ultimately, this review aims to support a new era of precision oncology, utilizing insights from epigenomics to improve prostate cancer patient outcomes.

Spatial deconvolution from bulk DNA methylation profiles determines intratumoral epigenetic heterogeneity

BackgroundIntratumoral heterogeneity emerges from accumulating genetic and epigenetic changes during tumorigenesis, which may contribute to therapeutic failure and drug resistance. However, the lack of a quick and convenient approach to determine the intratumoral epigenetic heterogeneity (eITH) limit the application of eITH in clinical settings. Here, we aimed to develop a tool that can evaluate the eITH using the DNA methylation profiles from bulk tumors.MethodsGenomic DNA of three laser micro-dissected tumor regions, including digestive tract surface, central bulk, and invasive front, was extracted from formalin-fixed paraffin-embedded sections of colorectal cancer patients. The genome-wide methylation profiles were generated with methylation array. The most variable methylated probes were selected to construct a DNA methylation-based heterogeneity (MeHEG) estimation tool that can deconvolve the proportion of each reference tumor region with the support vector machine model-based method. A PCR-based assay for quantitative analysis of DNA methylation (QASM) was developed to specifically determine the methylation status of each CpG in MeHEG assay at single-base resolution to realize fast evaluation of epigenetic heterogeneity.ResultsIn the discovery set with 79 patients, the differentially methylated CpGs among the three tumor regions were found. The 7 most representative CpGs were identified and subsequently selected to develop the MeHEG algorithm. We validated its performance of deconvolution of tumor regions in an independent cohort. In addition, we showed the significant association of MeHEG-based epigenetic heterogeneity with the genomic heterogeneity in mutation and copy number variation in our in-house and TCGA cohorts. Besides, we found that the patients with higher MeHEG score had worse disease-free and overall survival outcomes. Finally, we found dynamic change of epigenetic heterogeneity based on MeHEG score in cancer cells under the treatment of therapeutic drugs.ConclusionBy developing a 7-loci panel using a machine learning approach combined with the QASM assay for PCR-based application, we present a valuable method for evaluating intratumoral heterogeneity. The MeHEG algorithm offers novel insights into tumor heterogeneity from an epigenetic perspective, potentially enriching current knowledge of tumor complexity and providing a new tool for clinical and research applications in cancer biology.

SMARCB1-deficient malignant melanocytic uveal tumours: a new neural crest-derived tumour entity with SMARCB1-related germline predisposition.

Rhabdoid tumours (RT) are an aggressive malignancy affecting <2-year-old infants, characterised by biallelic loss-of-function alterations in SWI/SNF-related BAF chromatin remodelling complex subunit B1 (SMARCB1) in nearly all cases. Germline SMARCB1 alterations are found in ~30% of patients and define the RT Predisposition Syndrome type 1 (RTPS1). Uveal melanoma (UVM), the most common primary intraocular cancer in adults, does not harbour SMARCB1 alterations. We report two cases of a previously undescribed intraocular malignancy that shared some features with UVM and RT, but was also distinct from these entities. Both female patients, aged 23 and 14 years, underwent enucleation, and the tumours were subjected to comprehensive genomic, DNA methylation, and transcriptomic profiling. Pathological examination showed large, amelanotic intraocular tumours with epithelioid features, expressing melanocytic markers [S100P, SOX10, Melan-A, PMEL (HMB45), TYR] as seen using immunohistochemistry (IHC), but with little or no melanin production. Both tumours harboured biallelic loss-of-function SMARCB1 alterations, associated with loss of SMARCB1 (BAF47/INI1) expression on IHC. Their genomic profiles were atypical both for UVM and for RT, and no pathogenic variants were found in other genes tested, including those recurrently altered in UVM. In both patients, a germline SMARCB1 variant was found. However, there was no relevant family history of cancer. Transcriptome and methylome profiling suggested that these tumours were distinct from RT, UVM, and skin melanomas. RNAseq confirmed expression of early and late genes related to melanocytic differentiation. The first patient died of metastatic disease 16 months after diagnosis, the second was disease-free 10 months after completion of treatment. In summary, we report two cases of a previously undescribed, aggressive SMARCB1-deficient intraocular malignancy with melanocytic differentiation, which occurs in young patients, is distinct from UVM and RT, and expands the RTPS1 spectrum. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Comprehensive assessment of the significance of cellular senescence-associated genes in neuroblastoma.

The clinical course of high-risk neuroblastoma patients remains suboptimal, and the dynamic and reversible nature of cellular senescence provides an opportunity to develop new therapies. This study aims to identify unique markers of cellular senescence in neuroblastoma and to explore their clinical significance. The impact of multiple genetic regulatory mechanisms on cellular senescence-associated genes (CSAGs) was first assessed. We identified cellular senescence-associated subtypes by hierarchical clustering and explored the intrinsic differences between subtypes. We screened key CSAGs based on PPI networks and clinical significance. Subsequently, we constructed the cellular senescence-related risk score (CSRS) by LASSO regression and stepwise Cox regression, and validated its performance and stability through multiple methods. Finally, we performed single-cell analysis and constructed the nomogram. The expression of CSAGs was influenced by copy number variation and DNA methylation. We found that significant differences between cellular senescence-associated subtypes in immune infiltration and overall prognosis. AURKA, CDK4, TERT were key genes in the cellular senescence process. CSRS showed superior and robust predictive performance in several cohorts and could serve as an independent prognostic factor in neuroblastoma. The senescence signature was also meaningful at the single-cell level and the nomogram was shown to have high accuracy and high clinical benefit. We comprehensively evaluated the significance of cellular senescence in neuroblastoma and concluded that it was significantly associated with immune characteristics and overall prognosis. Based on the expression levels of CSAGs, we developed the CSRS, which was a reliable tool to contribute to prognostic assessment and clinical decision making.

Aberrant DNA methylation of EDNRB, MGMT and TIMP3 gene promoters in saliva of head and neck carcinoma patients as a diagnostic tool.

Differential DNA methylation in the promoter region of tumour suppressor genes leads to gene function silencing. In this study, we aimed to evaluate the salivary promoter methylation of EDNRB, MGMT and TIMP3 genes in H&NC patients (n = 100), premalignant lesions patients (n = 25) and healthy controls (n = 50). Blood and saliva samples were collected from all three groups and 20 concomitant tumour tissues were collected from the H&NC patients. Probe-based Methylation-specific PCR (MSP) was performed to assess the relative quantification of methylation. Significant promoter hypermethylation was detected in all three genes between H&NC patients vs. healthy controls and premalignant lesion patients vs. healthy controls. Spearman correlation analysis showed, no significant association between methylation levels and clinicopathological characteristics of HNC patients while tobacco smoking was significantly related to EDNRB methylation in premalignant lesions. The receiver operating curve (ROC) generated for EDNRB, MGMT and TIMP3 genes from saliva samples was able to differentiate between cancer vs. healthy controls and premalignant vs. healthy controls. The combined diagnostic efficiency of the panel was higher than the genes singly. The combined sensitivity of EDNRB and TIMP3 increased to 92%. This indicates that EDNRB and TIMP3 have potential value in clinical practice as effective diagnostic markers for H&NC using saliva samples.

Stochastic demethylation and redundant epigenetic suppressive mechanisms generate highly heterogeneous responses to pharmacological DNA methyltransferase inhibition

BackgroundDespite promising preclinical studies, the application of DNA methyltransferase inhibitors in treating patients with solid cancers has thus far produced only modest outcomes. The presence of intratumoral heterogeneity in response to DNA methyltransferase inhibitors could significantly influence clinical efficacy, yet our understanding of the single-cell response to these drugs in solid tumors remains very limited.MethodsIn this study, we used cancer/testis antigen genes as a model for methylation-dependent gene expression to examine the activity of DNA methyltransferase inhibitors and their potential synergistic effect with histone deacetylase inhibitors at the single-cancer cell level. The analysis was performed on breast cancer patient-derived xenograft tumors and cell lines, employing a comprehensive set of techniques, including targeted single-cell mRNA sequencing. Mechanistic insights were further gained through DNA methylation profiling and chromatin structure analysis.ResultsWe show that breast cancer tumors and cell cultures exhibit a highly heterogenous response to DNA methyltransferase inhibitors, persisting even under high drug concentrations and efficient DNA methyltransferase depletion. The observed variability in response to DNA methyltransferase inhibitors was independent of cancer-associated aberrations and clonal genetic diversity. Instead, these variations were attributed to stochastic demethylation of regulatory CpG sites and the DNA methylation-independent suppressive function of histone deacetylases.ConclusionsOur findings point to intratumoral heterogeneity as a limiting factor in the use of DNA methyltransferase inhibitors as single agents in treatment of solid cancers and highlight histone deacetylase inhibitors as essential partners to DNA methyltransferase inhibitors in the clinic.

Associations of maternal night shift work during pregnancy with DNA methylation in offspring: a meta-analysis in the PACE consortium

BackgroundNight shift work during pregnancy has been associated with differential DNA methylation in placental tissue, but no studies have explored this association in cord blood. We aimed to examine associations of maternal night shift work with cord blood DNA methylation.MethodsA total of 4487 mother–newborn pairs from 7 studies were included. Maternal night shift work during pregnancy was ascertained via questionnaires and harmonized into “any” versus “no”. DNA methylation was measured in cord blood using the Illumina Infinium Methylation arrays. Robust linear regression models adjusted for relevant confounders were run in the individual cohorts, and results were meta-analyzed.ResultsMaternal night shift work during pregnancy ranged from 3.4% to 26.3%. Three CpGs were differentially methylated in relation to maternal night shift work during pregnancy at a false discovery rate adjusted P < 0.05: cg10945885 (estimate (β) 0.38%, standard error (SE) 0.07), cg00773359 (β 0.25%, SE 0.05), and cg21836426 (β − 0.29%, SE 0.05). Associations of the identified CpGs were found in previous literature for gestational age and childhood and adolescent BMI. In a mouse model of prenatal jet lag exposure, information on offspring DNA methylation of ten homologous genes annotated to the 16 CpGs with P < 1 × 10−5 in our analysis was available, of which eight were associated (enrichment P: 1.62 × 10−11).ConclusionMaternal night shift work during pregnancy was associated with newborn DNA methylation at 3 CpGs. Top findings overlapped with those in a mouse model of gestational jet lag. This work strengthens evidence that DNA methylation could be a marker or mediator of impacts of circadian rhythm disturbances.

Epigenome-wide association study of objectively measured physical activity in peripheral blood leukocytes

BackgroundFew studies have explored the association between DNA methylation and physical activity. The aim of this study was to evaluate the association of objectively measured hours of sedentary behavior (SB) and moderate physical activity (MPA) with DNA methylation. We further aimed to explore the association between SB or MPA related CpG sites and cardiometabolic traits, gene expression, and genetic variation.ResultsFor discovery, we performed cross sectional analyses in pregnant women from the Epigenetics in pregnancy (EPIPREG) sample with both DNA methylation (Illumina MethylationEPIC BeadChip) and objectively measured physical activity data (SenseWear™ Pro 3 armband) (European = 244, South Asian = 109). For EWAS of SB and MPA, two main models were designed: model (1) a linear mixed model adjusted for age, smoking, blood cell composition, including ancestry as random intercept, and model (2) which was additionally adjusted for the total number of steps per day. In model 1, we did not identify any CpG sites associated with neither SB nor MPA. In model 2, SB was positively associated (false discovery rate, FDR < 0.05) with two CpG sites within the VSX1 gene. Both CpG sites were positively associated with BMI and were associated with several genetic variants in cis. MPA was associated with 122 significant CpG sites at FDR < 0.05 (model 2). We further analyzed the ten most statistically significant MPA related CpG sites and found that they presented opposite associations with sedentary behavior and BMI. We were not able to replicate the SB and MPA-related CpG sites in the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC had available objectively measured physical activity data from Actigraph (without steps/day available) and leucocyte DNA methylation data collected during adolescence (n = 408, European).ConclusionThis study suggests associations of objectively measured SB and MPA with maternal DNA methylation in peripheral blood leukocytes, that needs to be confirmed in larger samples of similar study design.

Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis

Transcription factors guide tissue development by binding to developmental stage-specific targets and establishing an appropriate enhancer landscape. In turn, DNA and chromatin modifications direct the genomic binding of transcription factors. However, how transcription factors navigate chromatin features to selectively bind a small subset of all the possible genomic target loci remains poorly understood. Here we show that Cdx2—a lineage defining transcription factor that binds distinct targets in developing versus adult intestinal epithelial cells—has a preferential affinity for a non-canonical CpG-containing motif in vivo. A higher frequency of this motif at embryonic Cdx2 targets and methylated state of the CpG during development enables selective Cdx2 binding and activation of developmental enhancers and genes. In adult cells, demethylation at these enhancers prevents ectopic Cdx2 binding, instead directing Cdx2 to its canonical motif without a CpG. This shift in Cdx2 binding facilitates Ctcf and Hnf4 recruitment, establishing super-enhancers during development and homeostatic enhancers in adult cells, respectively. Induced DNA methylation in adult mouse epithelium or cultured cells recruits Cdx2 to developmental targets, promoting corecruitment of partner transcription factors. Thus, Cdx2’s differential CpG motif preferences enable it to navigate distinct DNA methylation profiles, activating genes specific to appropriate developmental stages.

Multi-omics analysis reveals novel causal pathways in psoriasis pathogenesis

BackgroundTo elucidate the genetic and molecular mechanisms underlying psoriasis by employing an integrative multi-omics approach, using summary-data-based Mendelian randomization (SMR) to infer causal relationships among DNA methylation, gene expression, and protein levels in relation to psoriasis risk.MethodsWe conducted SMR analyses integrating genome-wide association study (GWAS) summary statistics with methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data. Publicly available datasets were utilized, including psoriasis GWAS data from the European Molecular Biology Laboratory–European Bioinformatics Institute and the UK Biobank. Heterogeneity in dependent instruments (HEIDI) test and colocalization analyses were performed to identify shared causal variants, and multi-omics integration was employed to construct potential regulatory pathways.ResultsOur analyses identified significant causal associations between DNA methylation, gene expression, protein abundance, and psoriasis risk. We discovered two pathways involving the long non-coding RNA RP11-977G19.11 and apolipoprotein F (APOF). Methylation at sites cg26804944 and cg02705573 was negatively associated with RP11-977G19.11 expression. Reduced expression of RP11-977G19.11 was linked to increased APOF levels, which were positively associated with a higher risk of psoriasis. Methylation at sites cg00172967, cg00294382, and cg24773560 was positively associated with RP11-977G19.11 expression. Elevated expression of RP11-977G19.11 was associated with decreased APOF levels, reducing the risk of psoriasis. Colocalization analysis highlighted APOF as a key protein in psoriasis pathogenesis. Validation using skin tissue, EBV-transformed lymphocytes data and inflammation-related protein panels confirmed the associations of RP11-977G19.11 and APOF with psoriasis.ConclusionsOur multi-omics analysis provides preliminary evidence for potential molecular mechanisms in psoriasis pathogenesis. Through the integration of GWAS and molecular QTL data, we identify candidate pathways that may be relevant to disease biology. While these findings require extensive experimental validation, they offer a framework for future investigations into the molecular basis of psoriasis.

On the Role of Epigenetic Modifications of HPA Axis in Post Traumatic Stress Disorder (PTSD) and Resilience.

Stress is a fundamental adaptive response mediated by the amygdala and Hypothalamus-Pituitary-Adrenal (HPA) axis. Extreme or chronic stress, however, can result in a multitude of neuropsychiatric disorders, including anxiety, paranoia, bipolar disorder (BP), major depressive disorder (MDD), and Post-Traumatic Stress Disorder (PTSD). Despite widespread exposure to trauma (70.4%), the incidence of PTSD is relatively low (6.8%), suggesting that either individual susceptibility or adaptability driven by epigenetic and genetic mechanisms are likely at play. PTSD takes hold from exposure to traumatic events, such as death threats or severe abuse, with its severity being impacted by the magnitude of trauma, it's frequency, and the nature. This comprehensive review examines how traumatic experiences and epigenetic modifications in hypothalamic pituitary axis (HPA), such as DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, are transmitted across generations, and impact genes like FKBP5, NR3C1, BDNF, and SLC6A4. It also provides a comprehensive overview on trauma reversal, resilience mechanisms, and pro-resilience factors such as HATs/HDACs ratio, DHEA/Cortisol ratio, testosterone levels, and neuropeptide Y, thus highlighting potential therapeutic approaches for trauma-related disorders. The studies highlighted here underscore the narrative, for the first time, that the examination and treatment of PTSD and other depressive disorders must invoke a multitude of approaches to seek out the most effective and personalized strategies. We also hope that the discussion emanating from this review will also inform government policies directed towards intergenerational trauma and PTSD.

Diagnostic impact of DNA methylation classification in adult and pediatric CNS tumors

Over the past decade, neuropathological diagnosis has undergone significant changes, integrating morphological features with molecular biomarkers. The molecular era has successfully refined neuropathological diagnostic accuracy; however, a substantial number of CNS tumor diagnoses remain challenging, particularly in children. DNA methylation classification has emerged as a powerful machine learning approach for clinical decision-making in CNS tumors. The aim of this study is to share our experience using DNA methylation classification in daily routine practice, illustrated through clinical cases. We employed a classification system to evaluate discrepancies between histo-molecular and DNA methylation diagnoses, with a specific focus on adult versus pediatric CNS tumors. In our study, we observed that 40% of cases fell into Class I, 47% into Class II, and 13% into Class III among the “matched cases” (≥ 0.84). In other words, DNA methylation classification confirmed morphological diagnoses in 63% of adult and 23% of pediatric cases. Refinement of diagnosis was particularly evident in the pediatric population (65% vs. 21% for the adult population, p = 0.006). Additionally, we discussed cases classified with low calibrated scores. In conclusion, our study confirms that DNA methylation classification provides significant added-value for CNS tumors diagnosis, particularly in pediatric cases.