Epigenomics最新文献

Adaptation to challenging environmental conditions is crucial for the survival/fitness of all organisms. Alongside genetic mutations that provide adaptive potential during environmental challenges, epigenetic modifications offer dynamic, reversible, and rapid mechanisms for regulating gene expression in response to environmental changes in both evolution and daily life, without altering DNA sequences or relying on accidental favorable mutations. The widespread conservation of diverse epigenetic mechanisms - like DNA methylation, histone modifications, and RNA interference across diverse species, including plants - underscores their significance in evolutionary biology. Remarkably, environmentally induced epigenetic alterations are passed to daughter cells and inherited transgenerationally through germline cells, shaping offspring phenotypes while preserving adaptive epigenetic memory. Throughout anthropoid evolution, epigenetic modifications have played crucial roles in: i) suppressing transposable elements and viral genomes intruding into the host genome; ii) inactivating one of the X chromosomes in female cells to balance gene dosage; iii) genetic imprinting to ensure expression from one parental allele; iv) regulating functional alleles to compensate for dysfunctional ones; and v) modulating the epigenome and transcriptome in response to influence from the gut microbiome among other functions. Understanding the interplay between environmental factors and epigenetic processes may provide valuable insights into developmental plasticity, evolutionary dynamics, and disease susceptibility.

Background: Necrotizing enterocolitis (NEC) is an often fatal intestinal injury that primarily affects preterm infants for which screening tools are lacking. We performed a pilot analysis of DNA methylation in peripheral blood samples from preterm infants with and without NEC to identify potential NEC biomarkers.

Methods: Peripheral blood samples were collected from infants at NEC diagnosis (n = 15) or from preterm controls (n = 13). Targeted genome-wide analysis was performed to identify DNA methylation differences between cases and controls.

Results: Broad differences between NEC cases and controls were identified in distinct genomic elements. Differences between surgical NEC cases and controls were frequently associated with inflammation. Deconvolution analysis to identify cell type-specific DNA signatures revealed increases in ileal, vascular endothelial, and cardiomyocyte cell type proportions and decreases in colonic and neuronal cell type proportions in blood from NEC cases relative to controls.

Conclusions: We identified marked differences in DNA methylation of peripheral blood samples from preterm infants with and without NEC. Increased ileal cell-specific methylation signatures in the blood of infants with NEC relative to controls, with a marked increase seen in surgical cases, provides rationale for further analysis of intestinal DNA methylation signatures as biomarkers of NEC.

Aim: Investigate associations between religion and spirituality (R&S) and DNA methylation of four HPA-axis genes (i.e. 14 CpG sites) among 992 adults from the Hispanic Community Health Study/Study of Latinos cohorts.

Methods: We assessed 1) the association between R&S measures and mean percent methylation overall and stratified by nativity status (US-born or immigrant) and 2) if interactions between R&S and methylation differed by nativity status.

Results: Among individuals with the FKBP5 CC genotype, increased spirituality scores were associated with significantly lower methylation levels among immigrants, compared to US-born participants. Organizational religiosity (e.g. service attendance) was associated with increased FKBP5 (CC genotype) methylation among immigrants.

Conclusion: R&S may influence HPA-axis functioning differently based on nativity status; a finding that could offer insight into mechanisms leading to health disparities.

Rare and undiagnosed diseases pose significant challenges for understanding their mechanisms, diagnosis, and treatment. The Triple Code Model, an integrative paradigm described here, considers the combined influence of the genetic code, epigenetic code, and nuclear structure (an emerging code), as fundamental biochemical mechanisms underlying many rare diseases. Studies demonstrate dysfunctional membrane and cytoplasmic signals instruct the epigenome to ultimately impact the 3D structure and dynamics of the nucleus, highlighting their close interrelationships. Consequently, this model offers a holistic perspective on rare and undiagnosed diseases by moving beyond a solely genetic view. We propose that this integrated framework will efficiently guide rare disease research by taking it 'Beyond the Base Pairs,' leading to improved diagnostics and personalized treatments.

Aims: Clustering algorithms have been widely applied to tumor DNA methylation datasets to define methylation-based cancer subtypes. This study aimed to evaluate the agreement between subtypes obtained from common clustering strategies.

Materials & methods: We used tumor DNA methylation data from 409 women with breast cancer from the Melbourne Collaborative Cohort Study (MCCS) and 781 breast tumors from The Cancer Genome Atlas (TCGA). Agreement was assessed using the adjusted Rand index for various combinations of number of CpGs, number of clusters and clustering algorithms (hierarchical, K-means, partitioning around medoids, and recursively partitioned mixture models).

Results: Inconsistent agreement patterns were observed for between-algorithm and within-algorithm comparisons, with generally poor to moderate agreement (ARI <0.7). Results were qualitatively similar in the MCCS and TCGA, showing better agreement for moderate number of CpGs and fewer clusters (K = 2). Restricting the analysis to CpGs that were differentially-methylated between tumor and normal tissue did not result in higher agreement.

Conclusion: Our study highlights that common clustering strategies involving an arbitrary choice of algorithm, number of clusters and number of methylation sites are likely to identify different DNA methylation-based breast tumor subtypes.

Cardiovascular diseases (CVDs) represent a prominent contributor to global morbidity and mortality rates, with projections indicating a rise in this burden due to population aging. While extensive research has underscored the efficacy of exercise in mitigating the risk of CVDs, the precise mechanisms, particularly within the realm of epigenetics, remain nascent. This article delves into cutting-edge research concerning exercise-induced epigenetic alterations and their impact on CVDs. Initially, we examine the cardiac implications stemming from exercise-induced epigenetic influences across varying intensities. Subsequently, our focus shifts toward delineating the mechanisms governing exercise-induced DNA methylation, lactylation modifications, and N6-methyladenosine (m6A) RNA modifications, alongside addressing associated challenges and outlining prospective research directions. These findings suggest that exercise-mediated epigenetic modifications offer promising therapeutic potential for the prevention and comorbidity management of CVDs. However, the heterogeneity and tissue specificity of these effects necessitate more targeted research to unlock their full therapeutic potential.

Aims, patients & methods: Dietary factors may regulate the epigenome. We aimed to explore whether a diet intervention, including excess sugar, affects the methylome in human sperm, and to describe the sperm methylome. We used Whole Genome Bisulfite Sequencing (WGBS) to analyze DNA methylation in sperm taken at three time points from 15 males during a diet intervention; i) at baseline, ii) after one week on a standardized diet, and iii) after an additional week on a high-sugar diet providing 150% of their estimated total energy expenditure.

Results: We identified seven nominal diet-associated differentially methylated regions in sperm (p < 0.05). The diet was nominally associated with methylation of 143 sites linked to fertility (e.g. AHRR, GNAS, and HDAC4), 313 sites in imprinted genes (e.g. GLIS3, PEG10, PEG3, and SNURF), and 42 sites in top 1%-expressed genes (e.g. CHD2) (p < 0.05). In sperm, 3'UTRs and introns had the highest levels of methylation, while 5'UTRs and CpG islands had the lowest levels. Non-expressed genes in human sperm were hypomethylated in exons compared with transcribed genes.

Conclusions: In human sperm, DNA methylation levels were linked to gene expression, and excess sugar had modest effects on methylation on imprinted and highly expressed genes, and genes affecting fertility.

p300 (E1A binding protein 300) and CBP (CREB-binding protein) are critical regulators of chromatin dynamics and gene expression, playing essential roles in various cellular processes, including proliferation, differentiation, apoptosis, and immune responses. These homologous histone acetyltransferases (HATs) function as transcriptional co-activators by acetylating histones and non-histone proteins. p300/CBP is essential for development, and dysregulation of p300 and CBP has been implicated in several human diseases, particularly cancer. Somatic mutations that inactivate p300/CBP are frequently observed across various cancer types. Additionally, other mutations leading to translocations or truncations of p300/CBP can result in enhanced catalytic activity, potentially representing novel gain-of-function mutations that promote tumor progression. In this review, we discuss the mechanisms underlying the regulation of p300/CBP HAT activity, its dysregulation in cancer, and the development of p300/CBP inhibitors and their potential in cancer therapies.

Background: Aggressive Variant Prostate Cancers (AVPCs) are incurable malignancies. Platinum-based chemotherapies are used for the palliative treatment of AVPC. The Polycomb Repressive Complex 2 (PRC2) promotes prostate cancer progression via histone H3 Lysine 27 tri-methylation (H3K27me3). EZH2 encodes the catalytic subunit of PRC2. A recently developed nucleosome capture technology (Nu.Q^Ⓡ).measures H3K27me3 levels in biological fluids. EZH2 inhibitors (EZH2i) are being tested in clinical trials. We hypothesize that epigenetic reprogramming via EZH2i improves the efficacy of Carboplatin in AVPC and that EZH2i activity can be measured via both cellular- and cell-free nucleosomal H3K27me3 (cf-H3K27me3) levels.

Methods: We studied the expression of PRC2 genes in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on cellular- and cf-H3K27me3 levels. We measured dose-dependent effects of Carboplatin with/without EZH2i on AVPC cell viability (IC₅₀). We used RNA-Seq to study how EZH2i modulates gene expression in AVPC cells.

Results: PRC2 genes were significantly up-regulated in AVPC vs other prostate cancer types. EZH2i reduced both cellular and cf-H3K27me3 levels. EZH2i significantly reduced Carboplatin IC₅₀. EZH2i reduced the expression of DNA repair genes and increased the expression of p53-dependent pro-apoptotic factors.

Conclusions: EZH2i plus Carboplatin is a promising combination treatment for AVPC.