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The aim of this study is to investigate students' meaning–making of multiple visual representations of epigenetics at different levels of biological organisation, and to discern what visual aspects of the multiple visual representations might influence students' reasoning. Adopting an exploratory approach, we analysed how students made meaning of visually communicated epigenetics phenomena while pointing at and reasoning about the multiple visual representations as part of semi-structured focus groups. We investigated students' meaning-making of the multiple visual representations by analysing their indications through physical pointing and accompanying verbal utterances. The analysis revealed meaning-making and the nature of linking between levels of organisation in four distinct patterns, namely intra horizontal linking, inter horizontal linking, one level vertical linking and two level vertical linking. In addition, five different visual characteristics of the multiple visual representations emerged as influencing students' reasoning while linking between different organisation levels: multiple visual representations, salient visual features, analogous visual features, familiar visual elements, and textual adjuncts. The study shows that multiple visual representations at different levels of organisation can support students' meaning-making of epigenetics, indicating that this way of communicating can be transferable to other biological domains. Potential implications for future research and teaching practice are provided. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: DNA 5‐formylcytosine (5fC) is a prominent epigenetic modification within biological systems. Recent investigations have shed light on its pivotal role in governing cell fate, gene expression, and disease pathways. However, our comprehension of the precise control of the 5fC site structure to influence its functionality remains limited. In this study, we have successfully achieved precise control over 5fC activity by harnessing the interaction between streptavidin and biotin. This research underscores the potential application of interactions between biomacromolecules and small molecules in advancing the field of DNA epigenetic functional regulation. [ABSTRACT FROM AUTHOR]

Summary: Viroids are pathogenic noncoding RNAs that completely rely on their host molecular machinery to accomplish their life cycle. Several interactions between viroids and their host molecular machinery have been identified, including interference with epigenetic mechanisms such as DNA methylation. Despite this, whether viroids influence changes in other epigenetic marks such as histone modifications remained unknown. Epigenetic regulation is particularly important during pathogenesis processes because it might be a key regulator of the dynamism of the defense response.Here we have analyzed the changes taking place in Cucumis sativus (cucumber) facultative and constitutive heterochromatin during hop stunt viroid (HSVd) infection using chromatin immunoprecipitation (ChIP) of the two main heterochromatic marks: H3K9me2 and H3K27me3.We find that HSVd infection is associated with changes in both H3K27me3 and H3K9me2, with a tendency to decrease the levels of repressive epigenetic marks through infection progression. These epigenetic changes are connected to the transcriptional regulation of their expected targets, genes, and transposable elements. Indeed, several genes related to the defense response are targets of both epigenetic marks.Our results highlight another host regulatory mechanism affected by viroid infection, providing further information about the complexity of the multiple layers of interactions between pathogens/viroids and hosts/plants. [ABSTRACT FROM AUTHOR]

Background: iPSC reprogramming technology exhibits significant promise in the realms of clinical therapeutics, disease modeling, pharmaceutical drug discovery, and various other applications. However, the extensive utilization of this technology has encountered impediments in the form of inefficiency, prolonged procedures, and ambiguous biological processes. Consequently, in order to improve this technology, it is of great significance to delve into the underlying mechanisms involved in iPSC reprogramming. The BET protein BRD4 plays a crucial role in the late stage of reprogramming; however, its precise function in the early stage remains unclear. Results: Our study aims to investigate BRD4's role in the early stages of iPSC reprogramming. Our investigation reveals that early inhibition of BRD4 substantially enhances iPSC reprogramming, whereas its implementation during the middle-late stage impedes the process. During the reprogramming, ribosome DNA expression initially increases before decreasing and then gradually recovers. Early inhibition of BRD4 improved the decline and restoration of rDNA expression in the early and middle-late stages, respectively. Additionally, we uncovered the mechanism of BRD4's regulation of rDNA transcription throughout reprogramming. Specifically, BRD4 interacts with UBF and co-localizes to both the rDNA promoter and enhancer regions. Ultimately, BRD4 facilitates rDNA transcription by promoting the enrichment of histone H3 lysine 27 acetylation in the surrounding chromatin. Moreover, we also discovered that early inhibition of BRD4 facilitates cells' transition out of the somatic cell state and activate pluripotent genes. Conclusions: In conclusion, our results demonstrate that early inhibition of BRD4 promotes sequential dynamic expression of rDNA, which improves iPSC reprogramming efficiency. [ABSTRACT FROM AUTHOR]

More than 100 RNA chemical modifications to cellular RNA have been identified. N6-methyladenosine (m6A) is the most prevalent modification of mRNA. RNA modifications have recently attracted significant attention due to their critical role in regulating mRNA processing and metabolism. tRNA and rRNA rank among the most heavily modified RNAs, and their modifications are essential for maintaining their structure and function. With our advanced understanding of RNA modifications, increasing evidence suggests RNA modifications are important in regulating various aspects of insect life. In this review, we will summarize recent studies investigating the impact of RNA modifications in insects, particularly highlighting the role of m6A in insect development, reproduction, and adaptation to the environment. [ABSTRACT FROM AUTHOR]

The frequencies and lengths of drought periods are increasing in subtropical and temperate regions worldwide. Epigenetic responses to water stress could be key for plant resilience to these largely unpredictable challenges. Experimental DNA demethylation, together with application of a stress factor is an appropriate strategy to reveal the contribution of epigenetics to plant responses to stress. We analysed leaf cytosine methylation changes in adult plants of the annual Mediterranean herb, Erodium cicutarium, in a greenhouse, after seed demethylation with 5‐Azacytidine and/or recurrent water stress. We used bisulfite RADseq (BsRADseq) and a newly reported reference genome for E. cicutarium to characterize methylation changes in a 2 × 2 factorial design, controlling for plant relatedness. In the long term, 5‐Azacytidine treatment alone caused both hypo‐ and hyper‐methylation at individual cytosines, with substantial hypomethylation in CG contexts. In control conditions, drought resulted in a decrease in methylation in all but CHH contexts. In contrast, the genome of plants that experienced recurrent water stress and had been treated with 5‐Azacytidine increased DNA methylation level by ca. 5%. Seed demethylation and recurrent drought produced a highly significant interaction in terms of global and context‐specific cytosine methylation. Most methylation changes occurred around genic regions and within Transposable Elements. The annotation of these Differentially Methylated Regions associated with genes included several with a potential role in stress responses (e.g., PAL, CDKC, and ABCF), confirming an epigenetic contribution in response to stress at the molecular level. [ABSTRACT FROM AUTHOR]

The centromere, a chromosome locus defined by the histone H3-like protein centromeric protein A (CENP-A), promotes assembly of the kinetochore to bind microtubules during cell division. Centromere maintenance requires CENP-A to be actively replenished by dedicated protein machinery in the early G1 phase of the cell cycle to compensate for its dilution after DNA replication. Cyclin-dependent kinases (CDKs) limit CENP-A deposition to once per cell cycle and function as negative regulators outside of early G1. Antithetically, Polo-like kinase 1 (PLK1) promotes CENP-A deposition in early G1, but the molecular details of this process are still unknown. We reveal here a phosphorylation network that recruits PLK1 to the deposition machinery to control a conformational switch required for licensing the CENP-A deposition reaction. Our findings clarify how PLK1 contributes to the epigenetic maintenance of centromeres. [ABSTRACT FROM AUTHOR]

Emerging evidence that intrauterine exposures to environmental stressors can ‘programme’ epigenetic modifications in offspring, leading to long‐lasting health risks, has generated debate about whether prospective mothers have a specific ‘epigenetic’ moral responsibility. However, to date, proposals for maternal epigenetic responsibility have failed to grapple adequately with the uncertainty of scientific evidence, and specifically, whether the causal basis for intrauterine epigenetic effects is sufficiently established to ground claims of moral responsibility. Causality is widely considered a necessary condition for the attribution of moral responsibility. In this paper, we show that much foetal programming science in humans has yet to establish a causal epigenetic connection between intrauterine exposures and subsequent offspring health impacts. This research struggles to establish that the relationship between such exposures and offspring health risks is in fact causal, neither has it been able to evince the causal significance of exposures during pregnancy to such outcomes. We argue that these two challenges to establishing causality in foetal programming research seriously undercut the idea that prospective mothers may have a moral responsibility to ensure the epigenetics of their offspring. [ABSTRACT FROM AUTHOR]

Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate nonhistone proteins involved in nongenomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, nongenomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal hippocampus (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERβ agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Further, while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect appeared independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5 min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via nongenomic ER activity. Critically, this novel PCAF–ER interaction might exist as a male-specific mechanism supporting STM. [ABSTRACT FROM AUTHOR]

This opinion article highlights the critical role of laboratory medicine and emerging technologies in cardiovascular risk reduction through exposome analysis. The exposome encompasses all external and internal exposures an individual faces throughout their life, influencing the onset and progression of cardiovascular diseases (CVD). Integrating exposome data with genetic information allows for a comprehensive understanding of the multifactorial causes of CVD, facilitating targeted preventive interventions. Laboratory medicine, enhanced by advanced technologies such as metabolomics and artificial intelligence (AI), plays a pivotal role in identifying and mitigating these exposures. Metabolomics provides detailed insights into metabolic changes triggered by environmental factors, while AI efficiently processes complex datasets to uncover patterns and associations. This integration fosters a proactive approach in public health and personalized medicine, enabling earlier detection and intervention. The article calls for global implementation of exposome technologies to improve population health, emphasizing the need for robust technological platforms and policy-driven initiatives to seamlessly integrate environmental data with clinical diagnostics. By harnessing these innovative technologies, laboratory medicine can significantly contribute to reducing the global burden of cardiovascular diseases through precise and personalized risk mitigation strategies. [ABSTRACT FROM AUTHOR]

This article discusses a new method for diagnosing brain lymphoma using nanopore sequencing of cerebrospinal fluid (CSF). The study demonstrates the clinical application of this method in two cases of CNS lymphoma. The researchers adapted their fast-track unsupervised machine learning approach for cases with a differential diagnosis of lymphoma and other malignant brain tumors. The results showed that nanopore sequencing-derived methylation patterns can be used for next-day diagnosis and treatment initiation. This point-of-care protocol has the potential to significantly reduce neurological impairment through timely and non-invasive testing. [Extracted from the article]

Epigenetic modifications (methylation, acetylation, etc.) of core histones play a key role in regulation of gene expression. Thus, the epigenome changes strongly during various biological processes such as cell differentiation and dedifferentiation. Classical methods of analysis of epigenetic modifications such as mass-spectrometry and chromatin immuno-precipitation, work with fixed cells only. Here we present a genetically encoded fluorescent probe, MPP8-Green, for detecting H3K9me3, a histone modification associated with inactive chromatin. This probe, based on the chromodomain of MPP8, allows for visualization of H3K9me3 epigenetic landscapes in single living cells. We used this probe to track changes in H3K9me3 landscapes during the differentiation of induced pluripotent stem cells (iPSCs) into induced neurons. Our findings revealed two major waves of global H3K9me3 reorganization during 4-day differentiation, namely on the first and third days, whereas nearly no changes occurred on the second and fourth days. The proposed method LiveMIEL (Live-cell Microscopic Imaging of Epigenetic Landscapes), which combines genetically encoded epigenetic probes and machine learning approaches, enables classification of multiparametric epigenetic signatures of single cells during stem cell differentiation and potentially in other biological models. [ABSTRACT FROM AUTHOR]

In this issue of Neuron , Torres-Berrío et al. 1 show that stress-susceptible mice exhibit elevated H3K27me1 levels in nucleus accumbens neurons due to the action of the SUZ12 VEFS domain, strengthening the link between specific epigenetic changes and long-lasting stress-induced social, emotional, and cognitive alterations. In this issue of Neuron , Torres-Berrío et al. show that stress-susceptible mice exhibit elevated H3K27me1 levels in nucleus accumbens neurons due to the action of the SUZ12 VEFS domain, strengthening the link between specific epigenetic changes and long-lasting stress-induced social, emotional, and cognitive alterations. [ABSTRACT FROM AUTHOR]

Mutating replication-dependent (RD) histone genes is an important tool for understanding chromatin-based epigenetic regulation. Deploying this tool in metazoans is particularly challenging because RD histones in these organisms are typically encoded by many genes, often located at multiple loci. Such gene arrangements make the ability to generate homogenous histone mutant genotypes by site-specific gene editing quite difficult. Drosophila melanogaster provides a solution to this problem because the RD histone genes are organized into a single large tandem array that can be deleted and replaced with transgenes containing mutant histone genes. In the last ∼15 years several different RD histone gene replacement platforms were developed using this simple strategy. However, each platform contains weaknesses that preclude full use of the powerful developmental genetic capabilities available to Drosophila researchers. Here we describe the development of a newly engineered platform that rectifies many of these weaknesses. We used CRISPR to precisely delete the RD histone gene array (HisC), replacing it with a multifunctional cassette that permits site-specific insertion of either one or two synthetic gene arrays using selectable markers. We designed this cassette with the ability to selectively delete each of the integrated gene arrays in specific tissues using site-specific recombinases. We also present a method for rapidly synthesizing histone gene arrays of any genotype using Golden Gate cloning technologies. These improvements facilitate the generation of histone mutant cells in various tissues at different stages of Drosophila development and provide an opportunity to apply forward genetic strategies to interrogate chromatin structure and gene regulation. [ABSTRACT FROM AUTHOR]

Early embryonic development is crucially important but also remarkably diverse among animal taxa. Axis formation and cell lineage specification occur due to both spatial and temporal control of gene expression. This complex system involves various signaling pathways and developmental genes such as transcription factors as well as other molecular interactants that maintain cellular states, including several types of epigenetic marks. 5mC DNA methylation, the chemical modification of cytosines in eukaryotes, represents one such mark. By influencing the compaction of chromatin (a high‐order DNA structure), DNA methylation can either repress or induce transcriptional activity. Mammals exhibit a reprogramming of DNA methylation from the parental genomes in the zygote following fertilization, and later in primordial germ cells (PGCs). Whether these periods of methylation reprogramming are evolutionarily conserved, or an innovation in mammals, is an emerging question. Looking into these processes in other vertebrate lineages is thus important, and teleost fish, with their extensive species richness, phenotypic diversity, and multiple rounds of whole genome duplication, provide the perfect research playground for answering such a question. This review aims to present a concise state of the art of DNA methylation reprogramming in early development in fish by summarizing findings from different research groups investigating methylation reprogramming patterns in teleosts, while keeping in mind the ramifications of the methodology used, then comparing those patterns to reprogramming patterns in mammals. [ABSTRACT FROM AUTHOR]

Background: Here, we evaluated whether the histone lysine demethylase 5B (JARID1B), is involved in osteogenic phenotype commitment of periodontal ligament cells (PDLCs), by considering their heterogeneity for osteoblast differentiation. Materials and Methods: Epigenetic, transcriptional, and protein levels of a gene set, involved in the osteogenesis, were investigated by performing genome‐wide DNA (hydroxy)methylation, mRNA expression, and western blotting analysis at basal (without osteogenic induction), and at the 3rd and 10th days of osteogenic stimulus, in vitro, using PDLCs with low (l) and high (h) osteogenic potential as biological models. Results: h‐PDLCs showed reduced levels of JARID1B, compared to l‐PDLCs, with significant inversely proportional correlations between RUNX2 and RUNX2/p57. Epigenetically, a significant reduction in the global H3K4me3 content was observed only in h‐PDLCs. Immunoblotting data reveal a significant reduction in the global H3K4me3 content, at 3 days of induction only in h‐PDLCs, while an increase in the global H3K4me3 content was observed at 10 days for both PDLCs. Additionally, positive correlations were found between global H3K4me3 levels and JARID1B gene expression. Conclusions: Altogether, our results show the crucial role of JARID1B in repressing PDLCs osteogenic phenotype and this claims to pre‐clinical protocols proposing JARID1B as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's Disease (PD) is a neurodegenerative disorder distinguished from other neurodegenerative disorders by the loss of dopaminergic neurons in the substantia nigra region of the brain, and is the most common neurodegenerative disorder, along with Alzheimer's Disease. PD is characterized by the presence of Lewy bodies when evaluated pathologically. Recent studies showed that the incidence of PH development as a result of genetic mutations alone is very low among all PD cases, and that environmental effects contribute significantly to the disease progression. The molecular mechanisms of diseases are associated with the maintenance of gene and protein expressions as a result of epigenetic regulations. The role of these regulations in the development and pathogenesis of neurodegenerative diseases is still not clearly understood. Methods: In our study, we examined the expression levels of H3C1, H3C12, HDAC4, HDAC5, ANKRD11, ANKRD12, ITM2B and GABBR1, which are genes involved in epigenetic processes in patients with idiopathic PD. Seventy five patients diagnosed with idiopathic PD and 50 healthy controls were included in the study. Peripheral Blood Mononuclear Cell (PBMC) was obtained from whole blood taken from the patient and control groups, and then total RNA was isolated from PBMC. Results: According to the comparison of the patient and control groups, the expression of H3C1, H3C12, ITM2B was high, and the expression of ANKRD11, HDAC4, HDAC5 and GABBR1 was low (p<0.05). Conclusion: As conclusion, we propose that histone regulation is one of the epigenetic mechanisms related to the presence of PD. [ABSTRACT FROM AUTHOR]

The Lys mutation of the canonical histone H3.1 Glu97 residue (H3E97K) is found in cancer cells. Previous biochemical analyses revealed that the nucleosome containing the H3E97K mutation is extremely unstable as compared to the wild‐type nucleosome. However, the mechanism by which the H3E97K mutation causes nucleosome instability has not been clarified yet. In the present study, the cryo‐electron microscopy structure of the nucleosome containing the H3E97K mutation revealed that the entry/exit DNA regions of the H3E97K nucleosome are disordered, probably by detachment of the nucleosomal DNA from the H3 N‐terminal regions. This may change the intra‐molecular amino acid interactions with the replaced H3 Lys97 residue, inducing structural distortion around the mutated position in the nucleosome. Consistent with the nucleosomal DNA end flexibility and the nucleosome instability, the H3E97K mutation exhibited reduced binding of linker histone H1 to the nucleosome, defective activation of PRC2 (the essential methyltransferase for facultative heterochromatin formation) with a poly‐nucleosome, and enhanced nucleosome transcription by RNA polymerase II. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality, affecting people of all races, ages, and sexes. Substantial sex dimorphism exists in the prevalence, manifestation, and outcomes of CVDs. Understanding the role of sex hormones as well as sex-hormone-independent epigenetic mechanisms could play a crucial role in developing effective and sex-specific cardiovascular therapeutics. Existing research highlights significant disparities in sex hormones, epigenetic regulators, and gene expression related to cardiac health, emphasizing the need for a nuanced understanding of these variations between men and women. Despite these differences, current treatment approaches for CVDs often lack sex-specific considerations. A pivotal shift toward personalized medicine, informed by comprehensive insights into sex-specific DNA methylation, histone modifications, and non-coding RNA dynamics, holds the potential to revolutionize CVD management. By understanding sex-specific epigenetic complexities, independent of sex hormone influence, future cardiovascular research can be tailored to achieve effective diagnostic and therapeutic interventions for both men and women. This review summarizes the current knowledge and gaps in epigenetic mechanisms and sex dimorphism implicated in CVDs. [ABSTRACT FROM AUTHOR]

Genome compartments are shaped by epigenetic marks and nuclear structure tethering. The most dramatic compartment changes occur during cell differentiation or cancer progression, but minor compartment changes in response to stimuli can have important biological consequences. Compartmentalization is generally robust and reinforced by many factors. Some genomic regions exist in states that make them more prone to compartment shift. Gene expression, replication timing, DNA damage, and the physical properties of the nucleus can both influence and be affected by genome spatial compartmentalization. The spatial segregation of the genome into compartments is a major feature of 3D genome organization. New data on mammalian chromosome organization across different conditions reveal important information about how and why these compartments form and change. A combination of epigenetic state, nuclear body tethering, physical forces, gene expression, and replication timing (RT) can all influence the establishment and alteration of chromosome compartments. We review the causes and implications of genomic regions undergoing a 'compartment switch' that changes their physical associations and spatial location in the nucleus. About 20–30% of genomic regions change compartment during cell differentiation or cancer progression, whereas alterations in response to a stimulus within a cell type are usually much more limited. However, even a change in 1–2% of genomic bins may have biologically relevant implications. Finally, we review the effects of compartment changes on gene regulation, DNA damage repair, replication, and the physical state of the cell. [ABSTRACT FROM AUTHOR]

The pathophysiological mechanisms of postoperative delirium (POD) are still unclear, and there is no reliable biomarker to distinguish between those with and without POD. Our aim was to discover DNAm markers associated with POD in blood collected from patients before and after gastrointestinal surgery. We collected blood samples from 16 patients including 7 POD patients at three timepoints; before surgery (pre), the first and third postoperative days (day1 and day3). We measured differences in DNA methylation between POD and control groups between pre and day1 as well as between pre and day3 using the Illumina EPIC array method. Besides, enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also performed after excluding influence of common factors related to surgery and anesthesia. The results showed that pre and day1 comparisons showed that immune and inflammatory signals such as 'T-cell activation' were significantly different, consistent with our previous studies with non-Hispanic White subjects. In contrast, we found that these signals were not significant any more when pre was compared with day3. These results provide strong evidence for the involvement of inflammatory and immune-related epigenetic signals in the pathogenesis of delirium, including POD, regardless of ethnic background. These findings also suggest that DNAm, which is involved in inflammation and immunity, is dynamically altered in patients with POD. In summary, the present results indicate that these signals may serve as a new diagnostic tool for POD. [ABSTRACT FROM AUTHOR]

Hydroxyurea (HU) is the most common drug therapy for sickle cell disease (SCD). The clinical benefits of HU derive from its upregulation of fetal hemoglobin (HbF), which reduces aggregation of the mutated sickle hemoglobin protein (HbS) and reduces SCD symptoms and complications. However, some individuals do not respond to HU, or stop responding over time. Unfortunately, current understanding of the mechanism of action of HU is limited, hindering the ability of clinicians to identify those patients who will respond to HU and to optimize treatment for those receiving HU. Given that epigenetic modifications are essential to erythropoiesis and HbF expression, we hypothesize that some effects of HU may be mediated by epigenetic modifications, specifically DNA methylation. However, few studies have investigated this possibility and the effects of HU on DNA methylation remain relatively understudied. In this review, we discuss the evidence linking HU treatment to DNA methylation changes and associated gene expression changes, with an emphasis on studies that were performed in individuals with SCD. Overall, although HU can affect DNA methylation, research on these changes and their clinical effects remains limited. Further study is likely to contribute to our understanding of hematopoiesis and benefit patients suffering from SCD. [ABSTRACT FROM AUTHOR]

Psoriasis (PsO) is a chronic inflammatory skin condition, often accompanied by psoriatic arthritis (PsA) and linked to various comorbidities and increased mortality rates. This study aimed to explore the relationship between PsO and accelerated biological aging, specifically focusing on epigenetic DNA methylation clocks. Using a matched case-control design, 20 PsO cases were selected along with age, race, and sex-matched 20 controls without PsO from the Skin Disease Biorepository at Brown Dermatology, Inc, Providence, Rhode Island. Blood samples retrieved from both groups were analyzed for DNA methylation, and epigenetic ages were calculated using DNA methylation clocks, including Horvath, Hannum, Pheno, SkinBlood, and Grim ages. Generalized estimation equations were employed to test the differences in epigenetic and chronological ages between PsO cases and controls, as well as within various subgroups in comparison to their respective controls. There were no statistically significant differences in epigenetic ages between PsO cases and controls. However, notably, PsO cases with PsA demonstrated an accelerated PhenoAge, compared to their matched controls. This study represents a pioneering investigation into the potential link between PsO and epigenetic aging, shedding light on the possibility of accelerated epigenetic aging in PsA, possibly associated with heightened inflammatory burden. These findings emphasize the systemic impact of PsA on the aging process, prompting the need for deeper exploration into autoimmune pathways, inflammation, and epigenetic modifications underlying PsO pathogenesis and aging mechanisms. Larger-scale studies with diverse populations are imperative to discern PsO subgroups experiencing accelerated biological aging and decipher the intricate interplay between PsO, inflammation, and aging pathways. [ABSTRACT FROM AUTHOR]

Purpose: Task Group 121 – Effects of ionizing radiation exposure in offspring and next generations – is a task group under the Committee 1 of the International Commission on Radiological Protection (ICRP), approved by the Main Commission on 18th November 2021. The main goals of Task Group 121 are to (1) review and update the scientific literature of relevance to radiation-related effects in the offspring of parent(s) exposed to ionizing radiation in both human and non-human biota; (2) to assess preconceptional and intrauterine effects of radiation exposure and related morbidity and mortality; and, (3) to provide advice about the level of evidence and how to consider these preconceptional and postconceptional effects in the system of radiological protection for humans and non-human biota. Methods: The Task Group is reviewing relevant literature since Publication 90 'Biological effects after prenatal irradiation (embryo and fetus)' (2003) and will include radiation-related effects on future generations in humans, animals, and plants. This review will be conducted to account for the health effects on offspring and subsequent generations in the current system of radiological protection. Radiation detriment calculation will also be reviewed. Finally, preliminary recommendations will be made to update the integration of health effects in offspring and next generations in the system of radiological protection. Results: A Workshop, jointly organized by ICRP Task Group 121 and European Radiation Protection Research Platforms MELODI and ALLIANCE was held in Budapest, Hungary, from 31st May to 2nd June 2022. Participants discussed four important topics: (1) hereditary and epigenetic effects due to exposure of the germ cell line (preconceptional exposure), (2) effects arising from exposure of the embryo and fetus (intrauterine exposure), (3) transgenerational effects on biota, and (4) its potential impact on the system of radiological protection. Conclusions: Based on the discussions and presentations during the breakout sessions, newer publications, and gaps on the current scientific literature were identified. For instance, there are some ongoing systematic reviews and radiation epidemiology reviews of intrauterine effects. There are newer methods of Monte Carlo simulation for fetal dosimetry, and advances in radiation genetics, epigenetics, and radiobiology studies. While the current impact of hereditary effects on the global detriment was reported as small, the questions surrounding the effects of radiation exposure on offspring and the next generation are crucial, recurring, and with a major focus on exposed populations. This article summarizes the workshop discussions, presentations, and conclusions of each topic and introduces the special issue of the International Journal of Radiation Biology resulting from the discussions of the meeting. [ABSTRACT FROM AUTHOR]

A Task Group (TG121) of the International Commission on Radiological Protection (ICRP) Committee 1 was launched in 2021 to study the effects of ionizing radiation in offspring and next generations. In this report, we summarize the evidence of multi- and trans-generational effects in non-human biota species that was discussed at the ICRP workshop entitled "Effects of Ionizing Radiation Exposure in Offspring and Next Generations" in June 2022. Epigenetic changes, including changes in DNA methylation, have been observed in trans- and multi-generational irradiation studies in both plants and animals. There were also reports of changes in offspring survival and reproduction. The reported evidence for altered reproduction is an area of potential concern, due to possible effects at the population or ecosystem level. Different considerations are also discussed regarding non-human biota data, such as transferability of data between different species or extending knowledge to humans, differences in species radiosensitivity, the presence of adaptive responses, and dose reconstruction for exposures that occur across multiple generations. Overall, there is a diverse range of available data of the effects in non-human biota, and it will require careful consideration when incorporating this evidence into the system of radiological protection of humans and of the environment. [ABSTRACT FROM AUTHOR]

Introduction: Long‐read whole genome sequencing like Oxford Nanopore Technology, is increasingly being introduced in clinical settings. With its ability to simultaneously call sequence variation and DNA modifications including 5‐methylcytosine, nanopore is a promising technology to improve diagnostics of imprinting disorders. Methods: Currently, no tools to analyze DNA methylation patterns at known clinically relevant imprinted regions are available. Here we present NanoImprint, which generates an easily interpretable report, based on long‐read nanopore sequencing, to use for identifying clinical relevant abnormalities in methylation levels at 14 imprinted regions and diagnosis of common imprinting disorders. Results and conclusion: NanoImprint outputs a summarizing table and visualization plots displays methylation frequency (%) and chromosomal positions for all regions, with phased data color‐coded for the two alleles. We demonstrate the utility of NanoImprint using three imprinting disorder samples from patients with Beckwith‐Wiedemann syndrome (BWS), Angelman syndrome (AS) and Prader‐Willi syndrome (PWS). NanoImprint script is available from https://github.com/carolinehey/NanoImprint. [ABSTRACT FROM AUTHOR]

Maternal smoking during pregnancy (MSDP) may impact offspring biological (e.g., deoxyribonucleic acid methylation [DNAm]) and behavioral (e.g., attention-deficit/hyperactivity disorder hyperactive/impulsive [ADHD-HI] symptoms) development. There has been consistency in findings of differential methylation in global DNAm, and the specific genes AHRR, CYP1A1, CNTNAP2, MYO1G, and GFI1 in relation to MSDP. The current study aims to (a) replicate the associations of MSDP and DNAm in prior literature in middle childhood–adolescence (cross-sectionally) using a sibling-comparison design where siblings were discordant for MSDP (n = 328 families; Mage Sibling 1 = 13.02; Sibling 2 = 10.20), adjusting for prenatal and postnatal covariates in order to isolate the MSDP exposure on DNAm. We also (b) cross-sectionally explored the role of DNAm in the most robust MSDP–ADHD associations (i.e., with ADHD-HI) previously found in this sample. We quantified smoking exposure severity for each sibling reflecting time and quantity of MSDP, centered relative to the sibling pair's average (i.e., within-family centered, indicating child-specific effects attributable MSDP exposure) and controlling for the sibling average MSDP (i.e., between-family component, indicating familial confounding related to MSDP). We found that child-specific MSDP was associated with global DNAm, and CNTNAP2, CYP1A1, and MYO1G methylation after covariate adjustment, corroborating emerging evidence for a potentially causal pathway between MSDP and DNAm. There was some evidence that child-specific CNTNAP2 and MYO1G methylation partially explained associations between MSDP and ADHD-HI symptoms, though only on one measure (of two). Future studies focused on replication of these findings in a longitudinal genetic design could further solidify the associations found in the current study. Public Significance Statement: We found differential deoxyribonucleic acid methylation (DNAm) during middle childhood and adolescence for children exposed to maternal smoking during pregnancy compared to their unexposed sibling in a rigorously controlled study, and initial exploratory evidence that this differential DNAm may partly explain associations of maternal smoking during pregnancy with hyperactivity/impulsivity symptoms. These findings support DNAm as a key biological mechanism by which prenatal exposures exert long-term effects on children's development. [ABSTRACT FROM AUTHOR]

Children born less than 30 weeks gestational age (GA) are at high risk for neurodevelopmental delay compared to term peers. Prenatal risk factors and neonatal epigenetics could help identify preterm children at highest risk for poor cognitive outcomes. We aimed to understand the associations among cumulative prenatal risk, neonatal DNA methylation, and child cognitive ability at age 3 years, including whether DNA methylation mediates the association between prenatal risk and cognitive ability. We studied 379 neonates (54% male) born less than 30 weeks GA who had DNA methylation measured at neonatal intensive care unit discharge along with 3-year follow-up data. Cumulative prenatal risk was calculated from 24 risk factors obtained from maternal report and medical record and epigenome-wide neonatal DNA methylation was assayed from buccal swabs. At 3-year follow-up, child cognitive ability was assessed using the Bayley Scales of Infant and Toddler Development (third edition). Cumulative prenatal risk and DNA methylation at two cytosine–phosphate–guanines (CpGs) were uniquely associated with child cognitive ability. Using high-dimensional mediation analysis, we also identified differential methylation of 309 CpGs that mediated the association between cumulative prenatal risk and child cognitive ability. Many of the associated CpGs were located in genes (TNS3, TRAPPC4, MAD1L1, APBB2, DIP2C, TRAPPC9, DRD2) that have previously been associated with prenatal exposures and/or neurodevelopmental phenotypes. Our findings suggest a role for both prenatal risk factors and DNA methylation in explaining outcomes for children born preterm and suggest we should further study DNA methylation as a potential mechanism underlying the association between prenatal risk and child neurodevelopment. Public Significance Statement: Understanding what factors predict long-term developmental outcomes in children born less than 30 weeks gestation could help inform prevention and intervention efforts for this high-risk group. This study shows that prenatal risk factors and neonatal DNA methylation could help identify preterm children at high risk for poor cognitive outcomes at age 3 years. DNA methylation may also help explain some of the long-term effects of prenatal risk on child outcomes. [ABSTRACT FROM AUTHOR]

Emerging preclinical autism research has shown the therapeutic promise of pharmacological inhibitors for epigenetic enzymes, such as histone deacetylases (HDAC), euchromatic histone methyltransferases (EHMT), and lysine-specific histone demethylase 1A (LSD1). These interventions restore gene expression, synaptic function, and behavioral performance in autism models, highlighting a new strategy for autism treatment. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is a devastating early-onset refractory epilepsy syndrome caused by variants in the SCN1A gene. A disturbed GABAergic interneuron function is implicated in the progression to DS but the underlying developmental and pathophysiological mechanisms remain elusive, in particularly at the chromatin level. Induced pluripotent stem cells (iPSCs) derived from DS cases and healthy donors were used to model disease-associated epigenetic abnormalities of GABAergic development. Chromatin accessibility was assessed at multiple time points (Day 0, Day 19, Day 35, and Day 65) of GABAergic differentiation. Additionally, the effects of the commonly used anti-seizure drug valproic acid (VPA) on chromatin accessibility were elucidated in GABAergic cells. The distinct dynamics in the chromatin profile of DS iPSC predicted accelerated early GABAergic development, evident at D19, and diverged further from the pattern in control iPSC with continued differentiation, indicating a disrupted GABAergic maturation. Exposure to VPA at D65 reshaped the chromatin landscape at a variable extent in different iPSC-lines and rescued the observed dysfunctional development of some DS iPSC-GABA. The comprehensive investigation on the chromatin landscape of GABAergic differentiation in DS-patient iPSC offers valuable insights into the epigenetic dysregulations associated with interneuronal dysfunction in DS. Moreover, the detailed analysis of the chromatin changes induced by VPA in iPSC-GABA holds the potential to improve the development of personalized and targeted anti-epileptic therapies. [ABSTRACT FROM AUTHOR]

Background: miR-155 is involved in the generation and maintenance of inflammation and pain, endothelial function and immune system homeostasis, all functions that are relevant for migraine. The present study aims to assess the levels of miR-155 in migraine subtypes (episodic and chronic) in comparison to age- and sex-matched healthy controls. Methods: This is a cross-sectional, controlled, study involving three study groups: I) episodic migraine (n = 52, EM), II) chronic migraine with medication overuse (n = 44, CM-MO), and III) healthy controls (n = 32, HCs). We assessed the interictal gene expression levels of miR-155, IL-1β, TNF-α, and IL-10 in peripheral blood monocytes using rtPCR. The monocytic differentiation toward the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes was assessed in circulating monocytes with flow cytometry analysis and cell sorting. Results: miR-155 gene expression was higher in CM-MO group (2.68 ± 2.47 Relative Quantification - RQ) when compared to EM group (1.46 ± 0.85 RQ, p = 0.006) and HCs (0.44 ± 0.18 RQ, p = 0.001). In addition, miR-155 gene expression was higher in EM group when compared to HCs (p = 0.001). A multivariate analysis confirmed the difference between EM and CM-MO groups after correction for age, sex, smoking habit, preventive treatment, aura, presence of psychiatric or other pain conditions. We found higher gene expression of IL-1β, TNF-α, and lower gene expression of IL-10 in migraine participants when compared to HCs (p = 0.001 for all comparisons). TNF-α and IL-10 genes alterations were more prominent in CM-MO when compared to EM participants (p = 0.001). miR-155 positively correlated with IL-1β (p = 0.001) and TNF-α (p = 0.001) expression levels. Finally, in people with CM-MO, we described an up-regulated percentage of events in both M1 and M2 monocytic profiles. Conclusions: Our study shows for the first time a specific profile of activation of miR-155 gene expression levels in monocytes of selected migraine subpopulations, more pronounced in subjects with CM-MO. Interestingly, mir-155 expression correlated with markers of activation of the inflammatory and immune systems. The CM-MO subpopulation showed a peculiar increase of both pro-inflammatory and anti-inflammatory monocytes which worths further investigation. Trial registration: www.clinicaltrials.gov. (NCT05891808). [ABSTRACT FROM AUTHOR]

Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations. [ABSTRACT FROM AUTHOR]

The H2B.8 variant has been diverged from other variants by its extended N-terminal region that possesses a conserved domain. We generated transgenic Arabidopsis plants expressing H2B.9 (class I), H2B.5 (class II) and H2B.8 (class III) fused to GFP under the 35 S promoter and studied their nuclear distribution and function. H2B.8-GFP showed peculiar nuclear localization at chromocenters in all cell types examined, while H2B.5-GFP and H2B.9-GFP displayed various patterns often dependent on cell types. H2B variants faithfully assembled onto nucleosomes showing no effect on nuclear organization; H2B.8-GFP appeared as three distinct isoforms in which one isoform appeared to be SUMOylated. Interestingly, transient expression in protoplasts revealed H2B.8 nuclear localization distinct from transgenic plants as it was restricted to the nuclear periphery generating a distinctive ring-like appearance accompanied by nuclear size reduction. This unique appearance was abolished by deletion of the N-terminal conserved domain or when H2B.8-GFP is transiently expressed in ddm1 protoplasts. GFP-TRAP-coupled proteome analysis uncovered H2B.8-partner proteins including H2A.W.12, which characterizes heterochromatin. Thus, our data highlight H2B.8 as a unique variant evolved in angiosperms to control chromatin compaction/aggregation and uncover cis- and trans-regulatory elements underlying its nuclear distribution and function. [ABSTRACT FROM AUTHOR]

ABSTRACT In long‐lived tree populations, when environmental change outpaces rates of evolutionary adaptation, plasticity in traits related to stress tolerance, dormancy, and dispersal may be vital for preventing extinction. While a population's genetic background partly determines its ability to adapt to a changing environment, so too do the many types of epigenetic modifications that occur within and among populations, which vary on timescales orders of magnitude faster than the emergence of new beneficial alleles. Consequently, phenotypic plasticity driven by epigenetic modification may be especially critical for sessile, long‐lived organisms such as trees that must rely on this plasticity to keep pace with rapid anthropogenic environmental change. While studies have reported large effects of DNA methylation, histone modification, and non‐coding RNAs on the expression of stress‐tolerance genes and resulting phenotypic responses, little is known about the role of these effects in non‐model plants and particularly in trees. Here, we review new findings in plant epigenetics with particular relevance to the ability of trees to adapt to or escape stressors associated with rapid climate change. Such findings include specific epigenetic influences over drought, heat, and salinity tolerance, as well as dormancy and dispersal traits. We also highlight promising findings concerning transgenerational inheritance of an epigenetic ‘stress memory’ in plants. As epigenetic information is becoming increasingly easy to obtain, we close by outlining ways in which ecologists can use epigenetic information better to inform population management and forecasting efforts. Understanding the molecular mechanisms behind phenotypic plasticity and stress memory in tree species offers a promising path towards a mechanistic understanding of trees' responses to climate change. [ABSTRACT FROM AUTHOR]

The antiapoptotic protein BCL2A1 is highly, but very heterogeneously expressed in Diffuse Large B-cell Lymphoma (DLBCL). Particularly in the context of resistance to current therapies, BCL2A1 appears to play an important role in protecting cancer cells from the induction of cell death. Reducing BCL2A1 levels may have therapeutic potential, however, no specific inhibitor is currently available. In this study, we hypothesized that the signaling network regulated by epigenetic readers may regulate the transcription of BCL2A1 and hence that inhibition of Bromodomain and Extra-Terminal (BET) proteins may reduce BCL2A1 expression thus leading to cell death in DLBCL cell lines. We found that the mechanisms of action of acetyl-lysine competitive BET inhibitors are different from those of proteolysis targeting chimeras (PROTACs) that induce the degradation of BET proteins. Both classes of BETi reduced the expression of BCL2A1 which coincided with a marked downregulation of c-MYC. Mechanistically, BET inhibition attenuated the constitutively active canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway and inhibited p65 activation. Furthermore, signal transducer of activated transcription (STAT) signaling was reduced by inhibiting BET proteins, targeting another pathway that is often constitutively active in DLBCL. Both pathways were also inhibited by the IκB kinase inhibitor TPCA-1, resulting in decreased BCL2A1 and c-MYC expression. Taken together, our study highlights a novel complex regulatory network that links BET proteins to both NFκB and STAT survival signaling pathways controlling both BCL2A1 and c-MYC expression in DLBCL. [ABSTRACT FROM AUTHOR]

Biological mechanisms underlying anxiety proneness (AP), the tendency to react fearfully to stressors due to the belief that experiencing anxiety has harmful consequences, remain unclear. Epigenetic mechanisms, such as microRNAs (small, non‐coding RNAs 19–20 nucleotides long), may be contributory. This study investigated AP‐associated differences in microRNA expression among South African adolescents with variable exposure to childhood trauma (CT). AP was assessed using a composite score reflecting trait anxiety and anxiety sensitivity, while CT exposure was assessed with the Childhood Trauma Questionnaire. High‐quality total RNA (n = 88) extracted from whole blood underwent microRNA‐sequencing. Differential microRNA expression analysis was conducted with DESeq2 in R, messenger RNA target prediction analysis was performed using TargetScan and DIANA‐microT, and the DIANA mirPATH tool was used for KEGG pathway analysis. The majority of participants were female (75.86%) with an average age of 15 (±1.19) years. MicroRNA expression analysis identified upregulation of hsa‐miR‐28‐5p and downregulation of hsa‐miR‐502‐3p and hsa‐miR‐500a‐3p in high‐AP individuals, irrespective of CT. Four KEGG pathways, each with ≥10% of their constituent genes predicted to be targets of the differentially expressed microRNAs, were identified and were enriched for genes involved in calcineurin and glutamate signalling. These findings suggest that epigenetically mediated effects on neuronal function contribute to the molecular aetiology of AP. [ABSTRACT FROM AUTHOR]

Summary Bipolar disorder (BD) is a complex and severe mental illness that causes significant suffering to patients. In addition to the burden of depressive and manic symptoms, patients with BD are at an increased risk for metabolic syndrome (MetS). MetS includes factors associated with an increased risk of atherosclerotic cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), which may increase the mortality rate of patients with BD. Several studies have suggested a link between BD and MetS, which may be explained at an epigenetic level. We have focused on epigenetic mechanisms to review the causes of metabolic risk in BD. [ABSTRACT FROM AUTHOR]

Gastrointestinal cancer is the most common malignancy in humans, often accompanied by poor prognosis. N6-methyladenosine (m6A) modification is widely present in eukaryotic cells as the most abundant RNA modification. It plays a crucial role in RNA splicing and processing, nuclear export, translation, and stability. Human AlkB homolog 5 (ALKBH5) is a type of RNA demethylase exhibiting abnormal expression in various gastrointestinal cancers.It is closely related to the tumorigenesis, proliferation, migration, and other biological functions of gastrointestinal cancer. However, recent studies indicated that the role and mechanism of ALKBH5 in gastrointestinal cancer are complicated and even controversial. Thus, this review summarizes recent advances in elucidating the role of ALKBH5 as a tumor suppressor or promoter in gastrointestinal cancer. It examines the biological functions of ALKBH5 and its potential as a therapeutic target, providing new perspectives and insights for gastrointestinal cancer research. [ABSTRACT FROM AUTHOR]

Background: Adenosine-to-inosine (A-to-I) RNA editing is a co-/post-transcriptional modification introducing A-to-G variations in RNAs. There is extensive discussion on whether the flexibility of RNA editing exerts a proteomic diversification role, or it just acts like hardwired mutations to correct the genomic allele. Eusocial insects evolved the ability to generate phenotypically differentiated individuals with the same genome, indicating the involvement of epigenetic/transcriptomic regulation. Methods: We obtained the genomes of 104 Hymenoptera insects and the transcriptomes of representative species. Comparative genomic analysis was performed to parse the evolutionary trajectory of a regulatory Ile > Met auto-recoding site in Adar gene. Results: At genome level, the pre-editing Ile codon is conserved across a node containing all eusocial hymenopterans. At RNA level, the editing events are confirmed in representative species and shows considerable condition-specificity. Compared to random expectation, the editable Ile codon avoids genomic substitutions to Met or to uneditable Ile codons, but does not avoid mutations to other unrelated amino acids. Conclusions: The flexibility of Adar auto-recoding site in Hymenoptera is selectively maintained, supporting the flexible RNA editing hypothesis. We proposed a new angle to view the adaptation of RNA editing, providing another layer to explain the great phenotypical plasticity of eusocial insects. [ABSTRACT FROM AUTHOR]

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10–8), the intergenic region between VRTN and SYNDIG1L (Score = − 37.67, P = 2.25 × 10–9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10–8), PVRL2 (Score = 125.86, P = 1.64 × 10–9), TOMM40 (Score = − 18.58, P = 4.61 × 10–8), and APOE (Score = 75.12, P = 7.26 × 10–26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW. [ABSTRACT FROM AUTHOR]

Lactase persistence (LP) — the genetic trait that determines the continued expression of the enzyme lactase into adulthood — has undergone recent, rapid positive selection since the advent of animal domestication and dairying in some human populations. While underlying evolutionary explanations have been widely posited and studied, the molecular basis of LP remains less so. This review considers the genetic and epigenetic bases of LP. Multiple single‐nucleotide polymorphisms (SNPs) in an LCT enhancer in intron 13 of the neighbouring MCM6 gene are associated with LP. These SNPs alter binding of transcription factors (TFs) and likely prevent age‐related increases in methylation in the enhancer, maintaining LCT expression into adulthood to cause LP. However, the complex relationship between the genetics and epigenetics of LP is not fully characterised, and the mode of action of methylation quantitative trait loci (meQTLs) (SNPs affecting methylation) generally remains poorly understood. Here, we examine published LP data to propose a model describing how methylation in the LCT enhancer is prevented in LP adults. We argue that this occurs through altered binding of the TF Oct‐1 (encoded by the gene POU2F1) and neighbouring TFs GATA‐6 (GATA6), HNF‐3A (FOXA1) and c‐Ets1 (ETS1) acting in concert. We therefore suggest a plausible new model for LCT downregulation in the context of LP, with wider relevance for future work on the mechanisms of other meQTLs. [ABSTRACT FROM AUTHOR]

Background: Early gastric cancer is treated endoscopically, but patients require surveillance due to the risk of metachronous gastric lesions (MGLs). Epigenetic alterations, particularly aberrant DNA methylation in genes, such as MIR124-3, MIR34b/c, NKX6-1, EMX1, MOS and CDO1, have been identified as promising biomarkers for MGL in Asian populations. We aimed to determine whether these changes could predict MGL risk in intermediate-risk Caucasian patients. Methods: This case–cohort study included 36 patients who developed MGL matched to 48 patients without evidence of MGL in the same time frame (controls). Multiplex quantitative methylation-specific PCR was performed using DNA extracted from the normal mucosa adjacent to the primary lesion. The overall risk of progression to MGL was assessed using Kaplan–Meier and Cox proportional hazards model analyses. Results: MIR124-3, MIR34b/c and NKX6-1 were successfully analyzed in 77 samples. MIR124-3 hypermethylation was detected in individuals who developed MGL (relative quantification 78.8 vs 50.5 in controls, p = 0.014), particularly in females and Helicobacter pylori-negative patients (p = 0.021 and p = 0.0079, respectively). This finding was further associated with a significantly greater risk for MGL development (aHR = 2.31, 95% CI 1.03–5.17, p = 0.042). Similarly, NKX6-1 was found to be hypermethylated in patients with synchronous lesions (relative quantification 7.9 vs 0.0 in controls, p = 0.0026). A molecular-based methylation model incorporating both genes was significantly associated with a threefold increased risk for MGL development (aHR = 3.10, 95% CI 1.07–8.95, p = 0.037). Conclusions: This preliminary study revealed an association between MIR124-3 and NKX6-1 hypermethylation and the development of MGL in a Western population. These findings may represent a burden reduction and a greener approach to patient care. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) accounts for around 90% of all oral cancers and is the eighth most common cancer worldwide. Despite progress in managing OSCC, the overall prognosis remains poor, with a survival rate of around 50–60%, largely due to tumor size and recurrence. The challenges of late-stage diagnosis and limitations in current methods emphasize the urgent need for less invasive techniques to enable early detection and treatment, crucial for improving outcomes in this aggressive form of oral cancer. Research is currently aimed at unraveling tumor-specific metabolite profiles to identify candidate biomarkers as well as discover underlying pathways involved in the onset and progression of cancer that could be used as new targets for diagnostic and therapeutic purposes. Metabolomics is an advanced technological approach to identify metabolites in different sample types (biological fluids and tissues). Since OSCC promotes metabolic reprogramming influenced by a combination of genetic predisposition and environmental factors, including tobacco and alcohol consumption, and viral infections, the identification of distinct metabolites through screening may aid in the diagnosis of this condition. Moreover, studies have shown the use of metabolites during the catalysis of epigenetic modification, indicating a link between epigenetics and metabolism. In this review, we will focus on the link between environmental, genetic, and epigenetic influences in metabolomic alterations in OSCC. In addition, we will discuss therapeutic targets of tumor metabolism, which may prevent oral tumor growth, metastasis, and drug resistance. [ABSTRACT FROM AUTHOR]

The ability of living organisms to persist, grow, evolve and invade environments seemingly challenges physical laws. Emerging Autonomous Systems representing autocatalytic cycles constituted of energized components in a state of Dynamic Kinetic Stability feature some of these properties. These simple theoretical models can grow, can be transferred but need an initiation to emerge and can collapse. Moreover, they can undergo kinetic selection in a way consistent with Darwinian behaviour, though they lack the ability to undergo change. The mere existence of these systems and their open‐ended growth potential are proposed to constitute a transmissible factor of a non‐coded kind. The onset and selection of epigenetic factors may therefore have preceded that of genetic polymers. Here is addressed the question of how these systems may arise from the diversity exhibited by abiotic organic matter, sometimes associated with intractable mixtures, which may actually be useful in providing initiators. The Darwinian description of evolution may therefore be merged without critical discontinuity within an origin scenario. Accordingly, such a theory would rests solely on physicochemical laws beginning with the potential of emerging autonomous systems to compete and invade the space dimension, and to further develop along other available dimensions including variability and, possibly, cognition. [ABSTRACT FROM AUTHOR]

Genome-wide studies have demonstrated regulatory roles for diverse non-coding elements, but their precise and interrelated functions have often remained enigmatic. Addressing the need for mechanistic insight, we studied their roles in expression of Lhb which encodes the pituitary gonadotropic hormone that controls reproduction. We identified a bi-directional enhancer in gonadotrope-specific open chromatin, whose functional eRNA (eRNA2) supports permissive chromatin at the Lhb locus. The central untranscribed region of the enhancer contains an iMotif (iM), and is bound by Hmgb2 which stabilizes the iM and directs transcription specifically towards the functional eRNA2. A distinct downstream lncRNA, associated with an inducible G-quadruplex (G4) and iM, also facilitates Lhb expression, following its splicing in situ. GnRH activates Lhb transcription and increased levels of all three RNAs, eRNA2 showing the highest response, while estradiol, which inhibits Lhb, repressed levels of eRNA2 and the lncRNA. The levels of these regulatory RNAs and Lhb mRNA correlate highly in female mice, though strikingly not in males, suggesting a female-specific function. Our findings, which shed new light on the workings of non-coding elements and non-canonical DNA structures, reveal novel mechanisms regulating transcription which have implications not only in the central control of reproduction but also for other inducible genes. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease characterised by recurrent seizures with complex aetiology. Temporal lobe epilepsy, the most common form in adults, can be acquired following brain insults including trauma, stroke, infection or sustained status epilepticus. The mechanisms that give rise to the formation and maintenance of hyperexcitable networks following acquired insults remain unknown, yet an extensive body of literature points towards persistent gene and epigenomic dysregulation as a potential mediator of this dysfunction. While much is known about the function of specific classes of epigenetic regulators (writers and erasers) in epilepsy, much less is known about the enzymes, which read the epigenome and modulate gene expression accordingly. Here, we explore the potential role for the epigenetic reader bromodomain and extra‐terminal domain (BET) proteins in epilepsy. Using the intra‐amygdala kainic acid model of temporal lobe epilepsy, we initially identified widespread dysregulation of important epigenetic regulators including EZH2 and REST as well as altered BRD4 expression in chronically epileptic mice. BRD4 activity was also notably affected by epilepsy‐provoking insults as seen by elevated binding to and transcriptional regulation of the immediate early gene Fos. Despite influencing early aspects of epileptogenesis, blocking BET protein activity with JQ1 had no overt effects on epilepsy development in mice but did alter glial reactivity and influence gene expression patterns, promoting various neurotransmitter signalling mechanisms and inflammatory pathways in the hippocampus. Together, these results confirm that epigenetic reader activity is affected by epilepsy‐provoking brain insults and that BET activity may exert cell‐specific actions on inflammation in epilepsy. [ABSTRACT FROM AUTHOR]

Epigenetics mechanisms play a significant role in human diseases by altering DNA methylation status, chromatin structure, and/or modifying histone proteins. By modulating the epigenetic status, the expression of genes can be regulated without any change in the DNA sequence itself. Epigenetic drugs exhibit promising therapeutic efficacy against several epigenetically originated diseases including several cancers, neurodegenerative diseases, metabolic disorders, cardiovascular disorders, and so forth. Currently, a considerable amount of research is focused on discovering new drug molecules to combat the existing research gap in epigenetic drug therapy. A novel and efficient delivery system can be established as a promising approach to overcome the drawbacks associated with the current epigenetic modulators. Therefore, formulating the existing epigenetic drugs with distinct encapsulation strategies in nanocarriers, including solid lipid nanoparticles, nanogels, bio‐engineered nanocarriers, liposomes, surface modified nanoparticles, and polymer–drug conjugates have been examined for therapeutic efficacy. Nonetheless, several epigenetic modulators are untouched for their therapeutic potential through different delivery strategies. This review provides a comprehensive up to date discussion on the research findings of various epigenetics mechanism, epigenetic modulators, and delivery strategies utilized to improve their therapeutic outcome. Furthermore, this review also highlights the recently emerged CRISPR tool for epigenome editing. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodResultConclusionIncidence of ischemic stroke increased after natural disasters. Therefore, it is important to establish a means of identifying high-risk populations for incident stroke. We performed a prospective cohort study to examine whether these three cardiovascular disease-related miRNAs (miR-126, miR-197, and miR-223) are associated with incident stroke among elderly survivors of the Great East Japan Earthquake.This cohort study was conducted using the data of 1192 survivors of the Great East Japan Earthquake over 60-years old who underwent a health check-up in December 2011. We followed up participants to record stroke cases until the end of 2016. We measured serum miRNAs by quantitative real-time polymerase chain reaction. HRs for incident stroke were estimated by Cox proportional hazard regression analyses.The serum miR-197 level was significantly associated with the incident stroke; the HR per one standard deviation change in the miR-197 level was 1.65 (95% confidence interval: 1.19 − 2.30). In contrast, the levels of miR-126 and miR-223 were not associated with the incident stroke.We found that a higher miR-197 level is associated with an increased risk of incident stroke; thus, miR-197 is expected to be useful as a predictive biomarker. [ABSTRACT FROM AUTHOR]

Aging is associated with a progressive decline of brain function, and the underlying causes and possible interventions to prevent this cognitive decline have been the focus of intense investigation. The maintenance of neuronal function over the lifespan requires proper epigenetic regulation, and accumulating evidence suggests that the deterioration of the neuronal epigenetic landscape contributes to brain dysfunction during aging. Epigenetic aging of neurons may, however, be malleable. Recent reports have shown age-related epigenetic changes in neurons to be reversible and targetable by rejuvenation strategies that can restore brain function during aging. This review discusses the current evidence that identifies neuronal epigenetic aging as a driver of cognitive decline and a promising target of brain rejuvenation strategies, and it highlights potential approaches for the specific manipulation of the aging neuronal epigenome to restore a youthful epigenetic state in the brain. This review discusses neuronal epigenetic aging as a driver of cognitive decline with age and highlights potential interventions for targeted brain rejuvenation. [ABSTRACT FROM AUTHOR]

Introduction: Men with African ancestry have the highest incidence and mortality rates of prostate cancer (PCa) worldwide. Methods: This study aimed to identify differentially methylated genes between tumor vs. adjacent normal and aggressive vs. indolent PCa in 121 African American patients. Epigenome‐wide DNA methylation patterns in tumor DNA were assessed using the human Illumina Methylation EPIC V1 array. Results: Around 5,139 differentially methylated CpG‐sites (q < 0.01, lΔβl > 0.2) were identified when comparing normal vs. tumor, with an overall trend of hypermethylation in prostate tumors. Multiple representative differentially methylated regions (DMRs), including immune‐related genes, such as CD40, Galectin3, OX40L, and STING, were detected in prostate tumors when compared to adjacent normal tissues. Based on an epigenetic clock model, we observed that tumors' total number of stem cell divisions and the stem cell division rate were significantly higher than adjacent normal tissues. Regarding PCa aggressiveness, 2,061 differentially methylated CpG‐sites (q < 0.05, lΔβl >.05) were identified when the grade group (GG)1 was compared with GG4/5. Among these 2,061 CpG sites, 155 probes were consistently significant in more than one comparison. Among these genes, several immune system genes, such as COL18A1, S100A2, ITGA4, HLA‐C, and ADCYAP1, have previously been linked to tumor progression in PCa. Conclusion: Several differentially methylated genes involved in immune‐oncologic pathways associated with disease risk or aggressiveness were identified. In addition, 261 African American‐specific differentially methylated genes related to the risk of PCa were identified. These results can shedlight on potential mechanisms contributing to PCa disparities in the African American Population. [ABSTRACT FROM AUTHOR]