Epigenomics最新文献

Background: This study examined the association between epigenetic genome-wide DNA methylation with mechanism-based phenotypes of spinal pain from adolescence through early adulthood, accounting for confounders.

Research design and methods: We investigated the relationship between the timing of spinal pain at 14, 17, 22, and 27 years and blood DNA methylation at 17 years in the Raine Study Gen2 cohort. We analyzed three phenotypes of spinal pain (neck pain only, low back pain only, neck and low back pain) compared to participants with no spinal pain using linear mixed effects models.

Results: We identified four genome-wide significant loci (3 neck, 1 back), all at age 22, and none from the other time points or with the combined neck and low back pain. The top locus for neck pain age 22 was cg06573902 (β = 0.0058, p-value 1.34E^-8) in the gene TOP1 (DNA Topoisomerase I). The top locus for low back pain at age 22, was cg14080518 (β = 0.0072, p-value = 5.36E^-8), located in the gene SMURF1 (SMAD Specific E3 Ubiquitin Protein Ligase 1).

Conclusion: While more basic research is required, the existence of mechanistic links could facilitate better screening and novel management strategies for those with spinal pain.

There is no immunohistochemical or molecular marker to confirm the histologic diagnosis of pancreatic ductal adenocarcinoma (PDAC). This is particularly important in a scenario of unknown primary. Molecularly, PDAC is characterized by a limited set of driver mutations, and new predictive and prognostic markers are needed to guide novel therapies. Recent data show that DNA methylation profiles combined with complex machine learning algorithms are ideal tools to improve the diagnosis of PDAC. In addition, DNA methylation can be used to gain a deeper understanding of PDAC pathogenesis and further stratify this entity. Furthermore, exciting technologies have emerged, such as nanopore sequencing, which can be used to move these diagnostic tools from the postoperative to the intraoperative setting, or even as a liquid biopsy approach.

Background: Antihypertensives are often prescribed in a 'trial and error' mode in management of hypertension. Significant drug response variability for these antihypertensives affects the therapeutic efficacy and increases the chance of developing adverse reactions. The study aims to investigate the influence of antihypertensives on the DNA methylation and its possible role in drug response variability and adverse events.

Methods: The study evaluated the expression level of epigenetic genes, global DNA methylation, hydroxy-methylation level, and gene level differential methylation in in-vitro system post antihypertensive treatment.

Results: The epigenetic gene expression pattern upon amlodipine, enalapril, telmisartan, and metoprolol treatment indicated a drug, dosage, and duration-dependent expression of DNMTs and TETs. Global methylation and hydroxy-methylation patterns overlap with the gene expression patterns of DNMTs and TETs for amlodipine and telmisartan, but variability was observed with metoprolol and enalapril. Gene-specific methylation pattern revealed several drug and duration-specific differential methylated genes, which can potentially impact therapeutic outcomes and adverse events as evidenced by their HPO terms.

Conclusions: The study signifies that antihypertensives influence the methylation pattern and drug-induced differential methylation of certain genes which can potentially contribute to adverse effects while that in other genes may have therapeutic utility for other diseases.

Epigenetic dysregulation has been increasingly understood to be a key factor in the development of myeloid malignancies, often acting alongside genetic alterations to disrupt normal hematopoiesis. The inherent reversibility of epigenetic changes has provided an excellent opportunity for therapeutic intervention. Hypomethylating agents (HMA) preferentially alter gene expression in heavily methylated malignant myeloid cells by inhibiting DNA methyltransferases thereby altering gene expression. They have since become foundation therapies in myelodysplastic syndrome (MDS) and in older patients with acute myeloid leukemia (AML). However, complete responses to HMA monotherapy are limited and usually non-durable. In recent years, novel approaches have been sought to overcome resistance and expand the role of epigenetic therapies in MDS and AML as well as in less well-studied myeloid malignancies such as myeloproliferative neoplasms (MPNs) and MDS/MPN overlap syndromes. Combination regimens that synergistically pair HMAs or other epigenetically active therapeutics with agents targeting apoptosis, cellular metabolism, and immune evasion have also shown early promise in improving patient outcomes. Oral formulations of HMAs have made maintenance strategies more convenient and tolerable for patients, with demonstrated benefits in AML and ongoing investigations in MDS and post-transplant settings. This review will explore these novel therapeutic strategies in the treatment of myeloid malignancies.

Medulloblastoma is the most common malignant childhood brain tumor. The disease exhibits significant clinical and molecular heterogeneity which leads to significant differences in outcome. Although survival rates have improved in recent years, outcome for patients with high-risk disease remains poor and survival is associated with significant treatment associated morbidity. Traditional risk stratification was established largely on the basis of clinical and histological factors, but these are not sufficient to capture the full biologic complexity of the disease. Recent advances have underscored the role of DNA methylation as a powerful epigenetic biomarker for precise subgroup stratification and prognostic classification of medulloblastoma into four primary molecular subtypes: WNT, SHH, Group 3, and Group 4. This review summarizes mechanisms of DNA methylation in cancer biology, methylation profiling analytical approaches, and their application in delineating medulloblastoma subtypes. Specific attention is placed on the clinical utility of methylation-based classifiers for guiding therapeutic decisions and clinical trial design.

Sarcomas are heterogeneous malignant tumors originating from mesenchymal tissues, presenting substantial diagnostic and therapeutic challenges. The diverse genetic and epigenetic landscape provides significant heterogeneity and complexity to the disease, ultimately leading to poor outcomes for affected individuals, especially in metastatic diseases. As research in this field evolves, incorporating methylation profiling into routine clinical practice could significantly enhance the early diagnosis, risk stratification, and personalized treatment strategies for sarcoma patients. Moreover, the integration of advanced genetic techniques and ongoing upgradation in treatment strategies, predominantly those targeting methylation modifications, may lead to improved survival outcomes in sarcomas. We conducted a structured literature review using PubMed, Scopus, Embase, Google Scholar, and Web of Science, encompassing publications up to 30 November 2024. The search focused on DNA methylation in sarcoma pathogenesis, diagnostics, and therapeutics. Relevant articles were screened, and key findings were synthesized thematically. In this review, we provide a comprehensive insight into the role of DNA methylation in promoting sarcomas. We emphasize subtype-associated methylation patterns in sarcomas and their value as prognostic and diagnostic biomarkers, revealing their synergistic effects with the existing treatment regimens. Despite having preclinical outcomes, the translation of these therapies into clinical practice remains a challenge.

Aim: We compared signatures of epigenetic aging in amyotrophic lateral sclerosis (ALS) patients and healthy controls to investigate the role of potential confounders and genetic subgroups.

Methods: We used whole-blood methylome profiles for 5,146 ALS patients and 2,156 controls available for Project MinE. We predicted biological age with three generations of epigenetic clocks and estimated age acceleration by regressing our model on control individuals to evaluate case/control differences. To investigate the contribution of C9orf72 expansions, we regressed the model on C9orf72-negative ALS patients. The predicted DunedinPACE pace of aging and telomere length additionally characterized aging dynamics.

Results: We found that white blood cell type proportions confound the previously observed increase in the pace of biological aging in ALS. When correcting for cell counts, there is no evidence for accelerated epigenetic aging compared to controls, except for ALS patients with the C9orf72 repeat expansion. None of the epigenetic age acceleration scores contributed to survival.

Conclusion: Our study revealed no significant difference in the pace of biological agingbetween ALS patients and controls, except for ALS patients carrying the C9orf72 mutation. We emphasize the importance of altered white blood cell proportions in general ALS pathophysiology as opposed to accelerated aging per se.

Aims: MTHFR is a key enzyme in the one-carbon metabolic pathway, whose activity has been implicated in Down syndrome (DS) and in the development of congenital heart defects (CHDs). The main aim was to assess promoter methylation levels of the MTHFR gene in DS individuals, including those with congenital heart defects (DS-CHD+), and those without (DS-CHD-), as well as control subjects. We also investigated if common MTHFR polymorphisms, namely 677C > T and 1298A > C correlate with MTHFR promoter methylation levels.

Patients and methods: The study included 118 participants: 59 individuals with DS, 25 of which with CHD, and 59 age and gender matched controls. Genomic DNA was extracted from peripheral blood. Methylation-sensitive high-resolution melting and PCR - RFLP were used to assess methylation and genotyping.

Results: DS individuals showed significantly higher MTHFR methylation levels than controls (p < 0.0001). No difference in MTHFR methylation levels between DS-CHD+ and DS-CHD- individuals was observed (p = 0.38). MTHFR 677TT carriers showed higher mean MTHFR methylation levels than 677CC carriers (p < 0.05).

Conclusion: We observed a significant increase in MTHFR promoter methylation levels in DS individuals compared to controls. Folate metabolism could influence MTHFR methylation levels as shown indirectly by the association of the MTHFR 677C > T polymorphism.

The American Association of Anthropological Genetics (AAAG) paired with the American Association of Biological Anthropology (AABA) to put on a symposium at the 94th Annual AAABA meeting entitled, "Beyond the genome: Intergenerational inheritance through epigenetics and other pathways." The symposium was held at the Marriott Waterfront in Baltimore, Maryland, on 14 March 2025, and was organized by Dr. Amy Non. The symposium's 13 speakers covered topics including the value of unique study designs and rare ecological settings, contributions of animal models, mechanisms beyond traditional epigenetics, such as microchimerism, microbiomes, and bioactive molecules in milk. Speakers also addressed ethical considerations of studies of intergenerational inheritance, including misconceptions and overhype. The discussed approaches help address ongoing challenges in the field of epigenetics, including how to demonstrate lasting effects across generations, identify causal associations with early life exposures, and ensure accurate interpretation of findings.

Breast cancer is one of the most commonly diagnosed cancers worldwide and is a significant contributor to the global cancer burden. It is a clinically heterogeneous disease and reliable tools are needed to support treatment decisions, including patient risk, prediction of therapeutic response and monitoring patients throughout their cancer journey. DNA methylation alterations are an early occurring, highly pervasive and stable modification during tumorigenesis, making DNA methylation an attractive target for the development of biomarkers. In this review, we first provide an overview of DNA methylation and explore its role in cancer, with an emphasis on breast cancer. We then focus on the potential use of tissue- and blood-based DNA methylation biomarkers to inform clinical decision-making in breast cancer paradigms: diagnosis; disease sub-typing; prediction of therapy response to neoadjuvant chemotherapy, endocrine therapy and immunotherapy; prognosis; and the tumor microenvironment. We highlight the significant progress achieved over recent decades in the development of DNA methylation-based biomarkers for breast cancer care. We end by discussing how the integration of advanced research methodologies and bioinformatic tools, and their incorporation into liquid biopsy platforms and ctDNA assays, offer promising opportunities for these biomarkers to be widely adopted in clinical practice.