Epigenomics最新文献

Experimental models and epidemiological data suggest that environmental factors, for example, adverse nutrition prior to conception, can lead to phenotypes in offspring of exposed parents in the absence of continued exposure. As a result these phenotypes have been described as epigentically inherited. The mechanistic basis for such phenomena has not been established in most cases. In this review, we consider possible contributing mechanisms for environmentaly induced epigenetic inheritance, with a focus on maternally transmitted effects and by comparing to paradigms of epigenetic inheritance with a clear mechanistic understanding. Genomic imprinting has provided an important conceptual framework for how the epigenetic states of parental germlines can determine allelic expression in offspring, yet, generally speaking, imprinted genes appear resilient to epigenetic disruption from altered parental environments. Metastable epialleles are environmentally sensitive and variably expressed loci that can impact organism phenotype, but the nature of any epigenetic marker at these loci transferred to offspring is unclear. Studies of examples across these forms of epigenetic inheritance show predominant effects are mediated by oocyte factors involved inreprogramming of the genome post-fertilization, rather than direct effects on gametic DNA methylation, with the exception of genomic imprinting. The potential contribution of additional oocyte chromatin features to the specific liability of phenotypic effector genes and their potential to persist through this reprogramming, however, remains to be investigated.

Aims & methods: DNA methylation and genomic instability are critical drivers of cancer initiation and malignant progression. However, the roles of methylation aberrations and genomic instability in malignant progression have not been thoroughly investigated in intrahepatic cholangiocarcinoma (ICC). To address this, we identified differentially methylated regions (DMRs) and somatic copy number alterations (SCNAs) from 341 ICC samples across various stages.

Results: Our findings revealed that stages IAIB, II, IIIA, and IIIB exhibited comparable methylation changes, whereas stage IV ICC showed a pronounced accumulation of stage-specific methylation alterations. Leveraging these findings, we developed a classification model that effectively distinguished stage IV ICC from earlier stages with high accuracy using 15 DMRs. Furthermore, stage IV ICC exhibited slightly higher genomic instability, including an elevated aneuploidy score and a greater proportion of focal amplifications. We also observed a positive correlation between SCNA burden and DNA methylation entropy in the promoter, gene body, and CpG island regions, with the gene body of MDM2 serving as a notable example.

Conclusions: These findings highlight the potential of DNA methylation as a biomarker for metastasis diagnosis and the interplay between local genomic instability and aberrant methylation, emphasizing their synergistic roles in driving the evolutionary trajectory of ICC.

The impact of psychosocial stress on mental and physical health is well-documented. Adverse experiences that occur early in life are particularly impactful on later life health. Epigenetic modifications, such as DNA methylation, have been proposed as a possible mechanism to mediate the impact of childhood events on adult health outcomes. The development of epigenetic clocks to estimate epigenetic age has revealed many examples of epigenetic age acceleration (and deceleration) in association with exposure to psychosocial stressors. Furthermore, altered epigenetic aging has been associated with downstream health outcomes. Here studies are discussed that have reported associations of epigenetic aging with early-life exposure to psychosocial stressors, such as childhood abuse and neglect, and with later-life health outcomes, including increased mortality, morbidity, and disease risk. Protective factors that may mitigate the effect of psychosocial stress on epigenetic aging, and possibly enable reversal of epigenetic aging, are also discussed.

Advances in DNA methylation and artificial intelligence have led to new methods for assessing risk and diagnosing coronary heart disease (CHD), the leading cause of death. However, whether these technologies can also be harnessed to generate new pharmacotherapeutic agents or monitor the effectiveness of new or existing CHD therapies is unknown. In this perspective, we review the development of cardiac assessment technologies and the challenges that these older approaches attempted to address. We next describe Precision Epigenetic methods and describe their strengths and limitations, as well as the conceptual framework through which these tools operate. Finally, we discuss their potential application to the development and evaluation of new therapies for CHD and how Precision Epigenetic tools compare to existing testing modalities for CHD. We conclude that the future is bright for the use of Precision Epigenetic methods in cardiovascular medicine and suggest that their routine use could lead to faster, less expensive and more effective healthcare.

Background: Helicobacter pylori (H. pylori)-induced chronic atrophic gastritis (CAG) is a significant health concern. The role of microsomal triglyceride transfer protein (MTTP) in CAG progression has not been explored, presenting a critical knowledge gap in understanding H. pylori-induced CAG pathogenesis.

Methods: Sprague-Dawley rats and gastric epithelial cell line were infected with H. pylori to build CAG model. The mRNA and protein levels of DNA methyltransferase 1 (DNMT1), MTTP, and glutathione peroxidase 4 (GPX4) were measured by quantitative real-time PCR (RT-qPCR) and western blotting, respectively. Moreover, the localization of DNMT1 and MTTP was detected via immunohistochemistry. Furthermore, the pathological changes of gastric tissue were analyzed by HE staining.

Results: The MTTP expression was downregulated in CAG. Moreover, overexpression of MTTP in gastric epithelial cells could suppress the inflammatory response induced by H. pylori infection and ferroptosis by upregulating GPX4 expression. In addition, DNMT1 expression was upregulated in CAG and was negatively correlated with MTTP expression. Furthermore, DNMT1 could target MTTP promoter to activate methylation and downregulate MTTP expression.

Conclusion: DNMT1 downregulated the MTTP expression through methylation, and thus mediate inflammasome-ferroptosis processes via GPX4 in the H. pylori-induced CAG.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by challenges in social communication and the presence of repetitive behaviors, typically diagnosed in early childhood. In this review, we searched PubMed and Google Scholar databases for relevant articles. ASD displays considerable heterogeneity in symptomatology and is more common in males, though shifting demographics indicate rising rates among minority populations. Transposable elements (TEs), which constitute approximately 50% of the mammalian genome, are increasingly recognized for their contribution to neurodevelopmental disorders, including ASD. These mobile genetic elements can induce genomic instability and modulate gene expression, thereby influencing ASD pathology. Evidence suggests that specific TEs, such as L1 and Alu elements, can disrupt genes critical for neurodevelopment and contribute to the disorder's genetic complexity. Furthermore, prenatal environmental exposures may activate TEs, potentially contributing to neuroinflammation observed in ASD. While the precise regulatory roles of non-coding TEs in ASD are still under investigation and require careful interpretation, integrating epigenetic aging markers like epigenetic clocks holds promise for advancing the field. Future research focused on the intricate relationship between TEs, environmental factors, epigenetic mechanisms, and neurodevelopmental processes is essential for identifying novel biomarkers and therapeutic targets, ultimately improving early diagnosis and interventions for ASD.

Vitamin K2 refers to a subfamily of vitamin K isoforms known as Menaquinones and, therefore, indicated as MK-n, the "n" indicating the number of isoprene units present in the side chain. Like the other members of the Vitamin K family, K2 is an enzymatic cofactor for the γ-glutamyl carboxylase (GGCX). This enzyme's substrates, which carboxylate glutamic acid residues, are known as Vitamin K-dependent proteins (VKDPs). Besides being involved in bone homeostasis, vitamin K exerts its primary function in the coagulation process. More recently, a function of Vitamin K also in brain homeostasis has been claimed. In addition to these so-called "canonical" effects, recent research highlights the possibility that Vitamin K, particularly Vitamin K2 May 2001have or induce epigenetic effects through the modulation of DNA methylation, histone modifications, and microRNAs expression. This evidence seems particularly relevant in brain diseases, where epigenetics is gaining a central role as a modulator of multiple diseases-associated molecular metabolisms. The present review examines the recent literature (PubMed) to collect evidence for the role of Vitamin K2 in neurodegenerative diseases with the goal of fostering interest in its epigenetic potential.

Longitudinal studies now document how leukocyte telomere attrition and epigenetic aging may be accelerated in people with HIV (PWH), in particular, around the time of HIV acquisition, during primary HIV infection, and during untreated chronic HIV infection. Whether chronic low-level inflammation and epigenetic aging go hand in hand or may be partially independent continues to be investigated in PWH and other settings. Epigenetic age acceleration (EAA) in PWH has now clearly been shown to be potentially reversible during successful antiretroviral therapy (ART). These studies point to how the beneficial effects of modern ART also include EAA-decelerating effects that seem large enough to regard ART as a kind of epigenetic rejuvenation therapy. Progress in the field has been limited in part due to the high cost of assessing EAA based on DNA methylation measures ("epigenetic clocks"). Demonstration of the clinical relevance of EAA and its reversion by ART will depend on large studies associating EAA with cardiovascular events and other adverse aging-associated endpoints in PWH.