Understanding organismal responses to environmental change is a central goal of biology with profound implications for the conservation of biodiversity. Widespread evidence of epigenetic modifications in response to environmental stress, including those inherited across generations, has led to considerable speculation about their role in organismal responses to environmental change. Yet, the magnitude and fitness consequences of epigenetic marks carried beyond maternal inheritance are largely unknown. Here, we tested how transgenerational epigenetic inheritance (TEI) shapes the phenotypic response of Daphnia clones to the environmental stressor Microcystis. We split individuals from each of eight genotypes into exposure and control treatments (P0 generation) and tracked the fitness of their descendants to the F3 generation. We found transgenerational epigenetic exposure to Microcystis led to reduced survival and growth rates and no consistent effect on offspring production. TEI was associated with increases in trait variance, suggesting the potential for heritable bet hedging driven by TEI. Taken together, our results demonstrate that TEI causes substantial-but not adaptive-trait shifts, suggesting transgenerational adaptive plasticity may be rare.

Sex differences in immune system development and response to pathogens has been well documented, with females exhibiting more favorable outcomes for certain infections but a higher incidence of autoimmune disease compared to males. At least some of these sex differences are mediated by sex hormones, which signal through sex hormone receptors to remodel the regulatory chromatin landscape of cells. Here, we summarize the current knowledge of how sex hormone receptors remodel chromatin structure and epigenetic marks in different contexts in humans. As the epigenome is fundamental to specifying cell identity and function, and reflects past exposures, epigenetic variation can influence cellular responses to future stimuli. This has implications for susceptibility to infection and complex inflammatory disease in a range of hormone therapy settings, including gender-affirming hormone therapy in transgender people. Therefore, profiling of epigenetic marks in the context of gender-affirming hormone therapy is an important unexplored field of research.

Epigenetics plays a key role in cellular differentiation and maintaining cell identity, enabling cells to regulate their genetic activity without altering the DNA sequence. Epigenetic regulation occurs within the context of hierarchically folded chromatin, yet the interplay between the dynamics of epigenetic modifications and chromatin architecture remains poorly understood. In addition, it remains unclear what mechanisms drive the formation of rugged epigenetic patterns, characterised by alternating genomic regions enriched in activating and repressive marks. In this study, we focus on post-translational modifications of histone H3 tails, particularly H3K27me3, H3K4me3, and H3K27ac. We introduce a mesoscopic stochastic model that incorporates chromatin architecture and competition of histone-modifying enzymes into the dynamics of epigenetic modifications in small genomic loci comprising several nucleosomes. Our approach enables us to investigate the mechanisms by which epigenetic patterns form on larger scales of chromatin organisation, such as loops and domains. Through bifurcation analysis and stochastic simulations, we demonstrate that the model can reproduce uniform chromatin states (open, closed, and bivalent) and generate previously unexplored rugged profiles. Our results suggest that enzyme competition and chromatin conformations with high-frequency interactions between distant genomic loci can drive the emergence of rugged epigenetic landscapes. Additionally, we hypothesise that bivalent chromatin can act as an intermediate state, facilitating transitions between uniform and rugged landscapes. This work offers a powerful mathematical framework for understanding the dynamic interactions between chromatin architecture and epigenetic regulation, providing new insights into the formation of complex epigenetic patterns.

Toxic chemicals and epigenetic biomarkers associated with cancer have been used successfully in clinical diagnostic screening of feces and urine from individuals, but they have been underutilized in a global setting. We analyzed peer-reviewed literature to achieve the following: (i) compile epigenetic biomarkers of disease, (ii) explore whether research locations are geographically aligned with disease hotspots, and (iii) determine the potential for tracking disease-associated epigenetic biomarkers. Studies (n = 1145) of epigenetic biomarkers (n = 146) in urine and feces from individuals have established notable diagnostic potential for detecting and tracking primarily gastric and urinary cancers. Panels with the highest sensitivity and specificity reported more than once were SEPT9 (78% and 93%, respectively) and the binary biomarker combinations GDF15, TMEFF2, and VIM (93% and 95%), NDRG4 and BMP3 (98% and 90%), and TWIST1 and NID2 (76% and 79%). Screening for epigenetic biomarkers has focused on biospecimens from the U.S., Europe, and East Asia, whereas data are limited in regions with similar/higher disease incidence rates (i.e., data for New Zealand, Japan, and Australia for colorectal cancer). The epigenetic markers discussed here may aid in the future monitoring of multiple cancers from individual- to population-level scales by leveraging the emerging science of wastewater-based epidemiology (WBE).

Polycystic ovary syndrome (PCOS) is the leading cause of amenorrhea and anovulatory infertility in women of reproductive age. Both gene polymorphisms and tissue-specific epigenetic alterations, which determine gene transcription and translation dynamics in disease-states, strongly influence PCOS development. Particularly, promoter-proximal DNA methylation and microRNA expression changes show strong associations with follicular defects, suggesting post-transcriptional dysregulation of localized gene networks. Our recent methylome study and other studies, posit DNA methylation as a regulator of microRNA expression in PCOS. Here, we identified microRNAs, potentially regulated by DNA methylation, and investigated whether their altered expression influences target gene expression in the PCOS ovary. Using granulosa cell samples of women with PCOS and age-BMI matched controls, we evaluated the transcript levels of 14 microRNAs participating in different ovarian processes and assessed their CpG-DNA methylation levels. For 9 of these microRNAs, which revealed differential methylation consistent with their gene hypomethylation or hypermethylation profiles, we evaluated the expression of their predicted, proteincoding target transcripts. Our data indicated that microRNA hypermethylation and decreased transcription of miR-10b-5p, miR-127-3p, miR-5189, miR-410-3p and miR23a-3p were consistent with the upregulation of PTEN, MMP13, OLR1, TET3 and APAF1 in PCOS. Conversely, microRNA hypomethylation and increased expression of miR-140-5p, miR-182-3p, miR-200b-5p and miR-3687 were consistent with downregulation of FZD6, LRP6, ZEB1 and LDLR. However, these observations need robust validations in larger study cohorts complemented with functional and mechanistic studies. Overall, our study indicates that altered microRNA expression as a consequence of DNA methylation changes, may contribute to metabolic and reproductive dysfunction in PCOS.

Cancer hypoxia, a crucial characteristic of malignancy, ranging from practically non-hypoxic to severe, impacts gene expression, metabolism and mechanisms associated with tumor formation serves as a key obstacle in cancer therapy. It triggers a complex network of cell signaling pathways, such as the NF-κB, PI3K, mTOR/AKT,MAPK, HIF and their associated genes regulating the effects of the same. The onset and advancement of cancer are attributed to genetic and epigenetic modifications which are intrinsically related. Off late, it has been observed that in disease progression, the epigenetic modifications lead to gene mutations that in turn alter the epigenome, presenting a major hurdle in fabricating treatment strategies. However, theprogress in science and technology has led to the emergence of various surfacing omics and multi-view clustering algorithms, which offer unparalleled prospects for further subtyping cancers, enhancing the prognosis and treatment results of these subtypes, and comprehending crucial pathophysiological mechanisms across diverse molecular strata. Multi-omics has allowed scientists to gain a more comprehensive understanding of the various ways that cellular malfunction can lead to cancer. So, it becomes of utmost importance to firstly understand the epigenetic changes taking place in tumor hypoxia at gene level. This review sheds light on the role of HIF gene in hypoxic milieu and its relationship with mechanisms of cancer epigenetics. It further glances as to how omics approach can be used to study the oncogenic cellular changes and how bioinformatic tools aid in identification of complex gene networks involved in disease progression. Lastly, it glimpses through the benefits and shortcomings of the existing epi drug therapy and how it can be used in developing novel treatment options.

The pathophysiology of obstructive sleep apnea (OSA) and diabetes mellitus (DM) is still unknown, despite clinical reports linking the two conditions. After investigating potential roles for DM-related genes in the pathophysiology of OSA, our goal is to investigate the molecular significance of the condition. Machine learning is a useful approach to understanding complex gene expression data to find biomarkers for the diagnosis of OSA.

Differentially expressed analysis for OSA and DM data sets obtained from GEO were carried out firstly. Then four machine algorithms were used to screen candidate biomarkers. The diagnostic model was constructed based on key genes, and the accuracy was verified by ROC curve, calibration curve and decision curve. Finally, the CIBERSORT algorithm was used to explore immune cell infiltration in OSA.

There were 32 important genes that were considered to be related both in OSA and DM datasets by differentially expressed analysis. Through enrichment analysis, the majority of these genes are enriched in immunological regulation, oxidative stress response, and nervous system control. When consensus characteristics from all four approaches were used to predict OSA diagnosis, STK17A was thought to have a high degree of accuracy. In addition, the diagnostic model demonstrated strong performance and predictive value. Finally, we explored the immune cells signatures of OSA, and STK17A was strongly linked to invasive immune cells.

STK17A has been discovered as a gene that can differentiate between individuals with OSA and DM based on four machine learning methods. In addition to offering possible treatment targets for DM-induced OSA, this diagnostic approach can identify high-risk DM patients who also have OSA.

The molecular basis of adaptive evolution and cancer progression are both complex processes that share many striking similarities. The potential adaptive significance of environmentally-induced epigenetic changes is currently an area of great interest in both evolutionary and cancer biology. In the field of cancer biology intense effort has been focused on the contribution of stress-induced non-coding RNAs (ncRNAs) in the activation of epigenetic changes associated with elevated mutation rates and the acquisition of environmentally adaptive traits. Examples of this process are presented and combined with more recent findings demonstrating that stress-induced ncRNAs are transferable from somatic to germline cells leading to cross-generational inheritance of acquired adaptive traits. The fact that ncRNAs have been implicated in the transient adaptive response of various plants and animals to environmental stress is consistent with findings in cancer biology. Based on these collective observations, a general model as well as specific and testable hypotheses are proposed on how transient ncRNA-mediated adaptive responses may facilitate the transition to long-term biological adaptation in both cancer and evolution.

From the second half of the nineteenth-century treatment of "imbecile" children in Britain underwent significant change. Examining the period from 1870 to 1920 when imbecility became a discrete category, and a matter of concern in policy and practice, this paper focuses on conceptualizations around fright, idleness, morality, and parental mental state as behavioral, emotional, and psychological causes and attributions of "imbecility" in children. I view this in light of the Victorian emotional culture of "care and control," which was driven by a shift in cost-cutting and fear of the impact of "imbecile children" on society, justifying exclusions, defining boundaries, and driving change. In light of the legacy of the "deserving/undeserving paradigm" and "care and control" agenda propagated by the Poor Law established in 1834 in England (and in 1845 in Scotland), "idleness" and "immorality" implied a form of abnormality, while "fright" could cause abnormality, and all needed to be controlled. Furthermore "fright" was classified as an (external) emotional event or trigger that has a lasting impact, and an early indication of including psychological factors (in addition to somatic) in explanations of "deficiencies." Using the Scottish National Institution for the Education of Imbecile Children founded in 1862 and the Waifs and Strays Society for destitute children, established in London in 1881 as examples, I argue that concerns about the rise of "mental deficiency" in the late Victorian and Edwardian periods were driven by moral panic as a force for social control, and to a lesser extent, the concept of care.

Cell types are traditionally thought to be specified and stabilized by gene regulatory networks. Here, we explore how chromatin memory contributes to the specification and stabilization of cell states. Through pervasive, local, feedback loops, chromatin memory enables cell states that were initially unstable to become stable. Deeper appreciation of this self-stabilizing role for chromatin broadens our perspective of Waddington's epigenetic landscape from a static surface with islands of stability shaped by evolution, to a plasticine surface molded by experience. With implications for the evolution of cell types, stabilization of resistant states in cancer, and the widespread plasticity of complex life.

The safety of titanium dioxide (TiO2), widely used in foods and personal care products, has been of ongoing concern. Significant toxicity of TiO2 has been reported, suggesting a risk to human health. To evaluate its potential epigenotoxicity, the effect of exposure to a TiO2 product to which humans could be exposed on DNA methylation, a primary epigenetic mechanism, was investigated using two human cell lines (Caco-2 (colorectal) and HepG2 (liver)) relevant to human exposure. Global methylation was determined by enzyme-linked immunosorbent assay-based immunochemical analysis. Gene promoter methylation was evaluated using EpiTect Methyl II Signature PCR System Array technology. Expression of DNA methyltransferases, MBD2, and URHF1 was quantified by qRT-PCR. A decrease in global DNA methylation was observed in both cell lines. Across the cell lines, seven genes (BNIP3, DNAJC15, GADD45G, GDF15, INSIG1, SCARA3, and TP53) were identified in which promoters were methylated. Changes in promoter methylation were associated with gene expression. Results also revealed aberrant expression of regulatory genes, DNA methyltransferases, MBD2, and UHRF1. Findings from the study clearly demonstrate the impact of TiO2 exposure on DNA methylation in two cell types, supporting the potential involvement of this epigenetic mechanism in its biological responses. Hence, epigenetic studies are critical for complete assessment of potential risk from exposure.

Ovarian aging is a major health concern for women. Ovarian aging is associated with reduced health span and longevity. Mitochondrial dysfunction is one of the hallmarks of ovarian aging. In addition to providing oocytes with optimal energy, the mitochondria provide a co-substrate that drives epigenetic processes. Studies show epigenetic alterations, both nuclear and mitochondrial contribute to ovarian aging. Both, nuclear and mitochondrial genomes cross-talk with each other, resulting in two ways orchestrated anterograde and retrograde response that involves epigenetic changes in nuclear and mitochondrial compartments. Epigenetic alterations causing changes in metabolism impact ovarian function. Key mitochondrial co-substrate includes acetyl CoA, NAD+, ATP, and α-KG. Thus, enhancing mitochondrial function in aging ovaries may preserve ovarian function and can lead to ovarian longevity and reproductive and better health outcomes in women. This article describes the role of mitochondria-led epigenetics involved in ovarian aging and discusses strategies to restore epigenetic reprogramming in oocytes by preserving, protecting, or promoting mitochondrial function.

Plants can program and reprogram their genomes to create genetic variation and epigenetic modifications, leading to phenotypic plasticity. Although consequences of genetic changes are comprehensible, the basis for transgenerational inheritance of epigenetic variation is elusive. This review addresses contributions of external (environmental) and internal (genomic) factors to the establishment and maintenance of epigenetic memory during plant evolution, crop domestication, and modern breeding. Dynamic and pervasive changes in DNA methylation and chromatin modifications provide a diverse repertoire of epigenetic variation potentially for transgenerational inheritance. Elucidating and harnessing epigenetic inheritance will help us develop innovative breeding strategies and biotechnological tools to improve crop yield and resilience in the face of environmental challenges. Beyond plants, epigenetic principles are shared across sexually reproducing organisms including humans with relevance to medicine and public health.

Epitranscriptomics is a rapidly evolving field that explores chemical modifications in RNA and how they contribute to dynamic and reversible regulations of gene expression. These modifications, for example, N6-methyladenosine (m6A), are crucial in various RNA metabolic processes, including splicing, stability, subcellular localization, and translation efficiency of mRNAs. Mass spectrometry-based proteomics has become an indispensable tool in unraveling the complexities of epitranscriptomics, offering high-throughput, precise protein identification, and accurate quantification of differential protein expression. Over the past two decades, advances in mass spectrometry, including the improvement of high-resolution mass spectrometers and innovative sample preparation methods, have allowed researchers to perform in-depth analyses of epitranscriptomic regulations. This review focuses on the applications of bottom-up proteomics in the field of epitranscriptomics, particularly in identifying and quantifying epitranscriptomic reader, writer, and eraser (RWE) proteins and in characterizing their functions, posttranslational modifications, and interactions with other proteins. Together, by leveraging modern proteomics, researchers can gain deep insights into the intricate regulatory networks of RNA modifications, advancing fundamental biology, and fostering potential therapeutic applications.

Aim: Longevity accumulating in families has genetic and epigenetic components. To study early and unbiased epigenetic predictors of longevity prospectively, a birth cohort would be ideal. However, the original family longevity selection score (FLoSS) focuses on populations of elderly only.Methods: In the German birth cohort KUNO-Kids we assessed when information for such scores may be best collected and how to calculate an adapted FLoSS.Results: A total of 551 families contributed to adapted FLoSS, with a mean score of -0.15 (SD 2.33). Adapted FLoSS ≥7 as a marker of exceptional longevity occurred in 3.3% of families, comparable to original FLoSS in elderly.Conclusion: An adapted FLoSS from data collectable postnatally may be a feasible tool to study unbiased epigenetic predictors for longevity.

The progressive degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) is accompanied by the formation of a broad array of cytoplasmic and nuclear neuronal inclusions (protein aggregates) largely containing RNA-binding proteins such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma/translocated in liposarcoma (FUS/TLS). This process is driven by a liquid-to-solid phase separation generally from proteins in membrane-less organelles giving rise to pathological biomolecular condensates. The formation of these protein aggregates suggests a fundamental alteration in the mRNA expression or the levels of the proteins involved. Considering the role of the epigenome in gene expression, alterations in DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA modifications become highly relevant to understanding how this pathological process takes effect. In this review, we explore the evidence that links epigenetic mechanisms with the formation of protein aggregates in ALS. We propose that a greater understanding of the role of the epigenome and how this inter-relates with the formation of pathological LLPS in ALS will provide an attractive therapeutic target.

The intensive applications of nanomaterials in the agroecosystem led to the creation of several environmental problems. More efforts are needed to discover new insights in the nanomaterial-microbe-plant nexus. This relationship has several dimensions, which may include the transport of nanomaterials to different plant organs, the nanotoxicity to soil microbes and plants, and different possible regulations. This review focuses on the challenges and prospects of the nanomaterial-microbe-plant nexus under agroecosystem conditions. The previous nano-forms were selected in this study because of the rare, published articles on such nanomaterials. Under the study's nexus, more insights on the carbon nanodot-microbe-plant nexus were discussed along with the role of the new frontier in nano-tellurium-microbe nexus. Transport of nanomaterials to different plant organs under possible applications, and translocation of these nanoparticles besides their expected nanotoxicity to soil microbes will be also reported in the current study. Nanotoxicity to soil microbes and plants was investigated by taking account of morpho-physiological, molecular, and biochemical concerns. This study highlights the regulations of nanotoxicity with a focus on risk and challenges at the ecological level and their risks to human health, along with the scientific and organizational levels. This study opens many windows in such studies nexus which are needed in the near future.

Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry. One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-m.o. male mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-m.o.) male mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed. To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young male mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

DNA methylation is one of the most important epigenetic mark involved in many physiologic cellular processes and pathologies. During mitosis, the transmission of DNA methylation patterns from a mother to the daughter cells is ensured through the action of the Ubiquitin-like, containing PHD and RING domains, 1/DNA methyltransferase 1 (UHRF1/DNMT1) tandem. UHRF1 is involved in the silencing of many tumor suppressor genes (TSGs) via mechanisms that remain largely to be deciphered. The present study investigated the role and the regulation of UHRF1 poly-ubiquitination induced by thymoquinone, a natural anti-cancer drug, known to enhance or re-activate the expression of TSGs. We found that the auto-ubiquitination of UHRF1, induced by TQ, is mediated by reactive oxygen species, and occurs following DNA damage. We demonstrated that the poly-ubiquitinated form of UHRF1 is K63-linked and can still silence the tumor suppressor gene p16INK4A/CDKN2A. We further showed that TQ-induced auto-ubiquitination is mediated via the activity of Tip60. Since this latter is known as a nuclear receptor co-factor, we investigated if the glucocorticoid receptor (GR) might be involved in the regulation of UHRF1 ubiquitination. Activation of the GR, with dexamethasone, did not influence auto-ubiquitination of UHRF1. However, we could observe that TQ induced a K48-linked poly-ubiquitination of GR, probably involved in the proteosomal degradation pathway. Mass-spectrometry analysis of FLAG-HA-tagged UHRF1 identified UHRF1 partners involved in DNA repair and showed that TQ increased their association with UHRF1, suggesting that poly-ubiquitination of UHRF1 is involved in the DNA repair process. We propose that poly-ubiquitination of UHRF1 serves as a scaffold to recruit the DNA repair machinery at DNA damage sites.

Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry. One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-m.o. mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-m.o.) mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed. To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.

Understanding processes that can produce adaptive phenotypic shifts in response to rapid environmental change is critical to reducing biodiversity loss. The ubiquity of environmentally induced epigenetic marks has led to speculation that epigenetic inheritance could potentially enhance population persistence in response to environmental change. Yet, the magnitude and fitness consequences of epigenetic marks carried beyond maternal inheritance are largely unknown. Here, we tested how transgenerational epigenetic inheritance (TEI) shapes the phenotypic response of Daphnia clones to the environmental stressor Microcystis. We split individuals from each of eight genotypes into exposure and control treatments (F0 generation) and tracked the fitness of their descendants to the F3 generation. We found transgenerational epigenetic exposure to Microcystis led to reduced rates of survival and individual growth and no consistent effect on offspring production. Increase in trait variance in the F3 relative to F0 generations suggests potential for heritable bet hedging driven by TEI, which could impact population dynamics. Our findings are counter to the working hypothesis that TEI is a generally adaptive mechanism likely to prevent extinction for populations inhabiting rapidly changing environments.

Although lineage reprogramming from one cell type to another is becoming a breakthrough technology for cell-based therapy, several limitations remain to be overcome, including the low conversion efficiency and subtype specificity. To address these, many studies have been conducted using genetics, chemistry, physics, and cell biology to control transcriptional networks, signaling cascades, and epigenetic modifications during reprogramming. Here, we summarize recent advances in cellular reprogramming and discuss future directions.

The hypothalamus in the brain plays a pivotal role in controlling energy balance in vertebrates. Nutritional excess through high-fat diet (HFD) feeding can dysregulate hypothalamic signaling at multiple levels. Yet, it remains largely unknown in what magnitude HFD feeding may impact epigenetics in this brain region. Here, it is shown that HFD feeding can significantly alter hypothalamic epigenetic events, including posttranslational histone modifications, DNA methylation, and chromatin accessibility. The authors comprehensively analyze the chromatin immunoprecipitation-sequencing (ChIP-seq), methylated DNA immunoprecipitation-sequencing (MeDIP-seq), single nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), and RNA-seq data of the hypothalamus of C57 BL/6 mice fed with a chow or HFD for 1 to 6 months. The chromatins are categorized into 6 states using the obtained ChIP-seq data for H3K4me3, H3K27ac, H3K9me3, H3K27me3, and H3K36me3. A 1-month HFD feeding dysregulates histone modifications and DNA methylation more pronouncedly than that of 3- or 6-month. Besides, HFD feeding differentially impacts chromatin accessibility in hypothalamic cells. Thus, the epigenetic landscape is dysregulated in the hypothalamus of dietary obesity mice.

The radiation protection community has been particularly attentive to the risks of delayed effects on offspring from low dose or low dose-rate exposures to ionizing radiation. Despite this, the current epidemiologic studies and scientific data are still insufficient to provide the necessary evidence for improving risk assessment guidelines. This literature review aims to inform future studies on multigenerational and transgenerational effects. It primarily focuses on animal studies involving in utero exposure and discusses crucial elements for interpreting the results. These elements include in utero exposure scenarios relative to the developmental stages of the embryo/fetus, and the primary biological mechanisms responsible for transmitting heritable or hereditary effects to future generations. The review addresses several issues within the contexts of both multigenerational and transgenerational effects, with a focus on hereditary perspectives.

Knowledge consolidation in the field of Developmental Origins of Health and Disease (DOHaD) has led us to propose a new study strategy. This strategy aims to address the transgenerational effects of in utero exposure to low dose and low dose-rate radiation. Within this concept, there is a possibility that disruption of epigenetic programming in embryonic and fetal cells may occur. This disruption could lead to metabolic dysfunction, which in turn may cause abnormal responses to future environmental challenges, consequently increasing disease risk. Lastly, we discuss methodological limitations in our studies. These limitations are related to cohort size, follow-up time, model radiosensitivity, and analytical techniques. We propose scientific and analytical strategies for future research in this field.

One of the central problems in epigenetics is how epigenetic modification patterns and chromatin structure are regulated in the cell nucleus. The polymer Potts model, a recently studied model of chromatins, is introduced with an offset in the interaction energy as a parameter, and the equilibrium properties are investigated using the mean-field analysis of the lattice model and molecular dynamics simulations of the off-lattice model. The results show that in common with both models, a phase emerges, which could be called the compact-disordered phase, in which the polymer conformation is compact and the epigenetic modification pattern is disordered, depending on the offset in the interaction energy and the fraction of the modified nucleosomes.

Epigenetic machinery is a cornerstone in normal cell development, orchestrating tissue-specific gene expression in mammalian cells. Aberrations in this intricate landscape drive substantial changes in gene function, emerging as a linchpin in cancer etiology and progression. While cancer was conventionally perceived as solely a genetic disorder, its contemporary definition encompasses genetic alterations intertwined with disruptive epigenetic abnormalities. This review explores the profound impact of DNA methylation, histone modifications, and noncoding RNAs on fundamental cellular processes. When these pivotal epigenetic mechanisms undergo disruption, they intricately guide the acquisition of the 6 hallmark characteristics of cancer within seemingly normal cells. Leveraging the latest advancements in decoding these epigenetic intricacies holds immense promise, heralding a new era in developing targeted and more efficacious treatment modalities against cancers driven by aberrant epigenetic modifications.

Epigenetic alterations are heritable and enduring modifications in gene expression that play a pivotal role in immune evasion. These include alterations to noncoding RNA, DNA methylation, and histone modifications. DNA methylation plays a crucial role in normal cell growth and development but alterations in methylation patterns such as hypermethylation or hypomethylation can enable tumor and viral cells to evade host immune responses. Histone modifications can also inhibit immune responses by promoting the expression of genes involved in suppressing normal immune function. In the case of T-cell lymphoma, adult T-cell lymphomas (ATL) also undergo immune evasion through the exceptional function of its accessory and regulatory genes. Epigenetic therapies are emerging as a promising adjunct to traditional immunotherapy and chemotherapy regimens. Clinical trials are currently investigating the use of epigenetic therapies in combination with immunotherapies and chemotherapies for more effective treatment of ATL and other cancers. This review highlights epigenetic alterations that are widely found in T-cell malignancies.

Background: Research has recently begun to examine the potential intergenerational impacts of trauma on obesity.Objective: This scoping review examines the literature on the interactions between intergenerational trauma, epigenetics, and obesity in Indigenous populations. The review was conducted to identify what is known from the literature about how intergenerational trauma may epigenetically influence obesity in Indigenous populations.Methods: Following the PRISMA-ScR guidelines for scoping reviews, online databases were used to identify studies that included discussion of the four focus topics: trauma, epigenetics, obesity, and Indigeneity. The review resulted in six studies that examined those themes. The focus and findings of the selected studies varied from cultural to biological mechanisms and from discussion regarding trauma, epigenetics, obesity, or Indigeneity, but they support three broad statements. First, they support that obesity has genetic and epigenetic factors. Second, intergenerational trauma is prevalent in Indigenous communities. Finally, intergenerational trauma has cultural and biological influences on obesity.Conclusions: Current literature illustrates that intergenerational trauma has behavioural and epigenetic influences that can lead to increased obesity. This scoping review provides a preliminary map of the current literature and understandings of these topics. This review calls for continued studies regarding the connection between trauma, obesity, and epigenetics in Indigenous communities. Future research is vital for practice and policy surrounding individual and communal healing.

Lung cancer is indeed a major cause of cancer-related deaths worldwide. The development of tumors involves a complex interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms, including DNA methylation (DNAm), histone modifications, and microRNA expression, play a crucial role in this process. Changes in DNAm patterns can lead to the silencing of important genes involved in cellular functions, contributing to the development and progression of lung cancer. MicroRNAs and exosomes have also emerged as reliable biomarkers for lung cancer. They can provide valuable information about early diagnosis and treatment assessment. In particular, abnormal hypermethylation of gene promoters and its effects on tumorigenesis, as well as its roles in the Wnt signaling pathway, have been extensively studied. Epigenetic drugs have shown promise in the treatment of lung cancer. These drugs target the aberrant epigenetic modifications that are involved in the development and progression of the disease. Several factors have been identified as drug targets in non-small cell lung cancer. Recently, combination therapy has been discussed as a successful strategy for overcoming drug resistance. Overall, understanding the role of epigenetic mechanisms and their targeting through drugs is an important area of research in lung cancer treatment.

Introduction: miR-21 is a critical microRNA for the regulation of various processes in oocytes and granulosa cells. It is involved in the modulation of apoptosis and can influence other epigenetic mechanisms. Among these mechanisms, DNA methylation holds significant importance, particularly during female gametogenesis. Evidence has demonstrated that microRNAs, including miR-21, can regulate DNA methylation. Bisphenol A (BPA) is a widespread chemical that disrupts oocyte maturation and granulosa cell function. Recent findings suggested that BPA can act through epigenetic pathways, including DNA methylation and microRNAs. Methods: This study uses anti-miR-21 LNAs to explore the involvement of miR-21 in the regulation of DNA methylation in bovine Cumulus-Oocyte-Complexes (COCs) and granulosa cells, in the presence and absence of BPA. This study investigated 5 mC/5hmC levels as well as gene expression of various methylation enzymes using qPCR and western blotting. Results and discussion: Results reveal that BPA reduces 5mC levels in granulosa cells but not in COCs, which can be attributed to a decrease in the methylating enzymes DNMT1 and DNMT3A, and an increase in the demethylating enzyme TET2. We observed a significant increase in the protein levels of DNMT1, DNMT3A, and TET2 upon inhibition of miR-21 in both COCs and granulosa cells. These findings directly imply a strong correlation between miR-21 signaling and the regulation of DNA methylation in bovine COCs and granulosa cells under BPA exposure.

Gene expression is tremendously altered in the brain during memory acquisition, recall, and forgetfulness. However, non-genetic factors, including environmental elements, epigenetic changes, and lifestyle, have grabbed significant attention in recent years regarding the etiology of neurodegenerative diseases (NDD) and age-associated dementia. Epigenetic modifications are essential in regulating gene expression in all living organisms in a DNA sequence-independent manner. The genes implicated in ageing and NDD-related memory disorders are epigenetically regulated by processes such as DNA methylation, histone acetylation as well as messenger RNA editing machinery. The physiological and optimal state of the epigenome, especially within the CNS of humans, plays an intricate role in helping us adjust to the changing environment, and alterations in it cause many brain disorders, but the mechanisms behind it still need to be well understood. When fully understood, these epigenetic landscapes could act as vital targets for pharmacogenetic rescue strategies for treating several diseases, including neurodegeneration- and age-induced dementia. Keeping this objective in mind, this updated review summarises the epigenetic changes associated with age and neurodegeneration-associated dementia.

Hypertension remains a major risk factor for myocardial infarction, heart failure, end-stage renal disease, and stroke. Multiple genes are involved in the process of hypertension with an additional dimension of interaction with the environment. This study conducted a bibliometric analysis of publications in the field of hypertension and epigenetics over the past 10 years to summarize the current status of the field and analyze the trends in the field.

On February 5, 2023, we chose the web of science core collection database as the study data source. VOS viewer 1.6.18 and Cite Space 6.1.6 were used to examine publications of research on hypertension and epigenetics that were published between 2013 and 2022. We looked through the papers for journals, organizations, nations and regions, authors, and key terms.

This analysis covered a total of 1535 papers on studies into hypertension and epigenetics. There were 7279 authors, 83 nations, 1983 organizations, and 606 journals in all of the articles. In the USA, 540 publications were the most. The institution with the most publications was Harvard Medical School. The author with the most articles was Zhao Lubo.

This study summarizes the global research trends in hypertension and epigenetics. Publications in this field have increased year by year in the last decade and the field of research on hypertension and epigenetics has good prospects for growth.

All the cells of an organism contain the same genome. However, each cell expresses only a minor fraction of its potential and, in particular, the genes encoding the proteins necessary for basal metabolism and the proteins responsible for its specific phenotype. The ability to use only the right and necessary genes involved in specific functions depends on the structural organization of the nuclear chromatin, which in turn depends on the epigenetic history of each cell, which is stored in the form of a collection of DNA and protein modifications. Among these modifications, DNA methylation and many kinds of post-translational modifications of histones play a key role in organizing the complex indexing of usable genes. In addition, non-canonical histone proteins (also known as histone variants), the synthesis of which is not directly linked with DNA replication, are used to mark specific regions of the genome. Here, we will discuss the role of the H3.3 histone variant, with particular attention to its loading into chromatin in the mammalian nervous system, both in physiological and pathological conditions. Indeed, chromatin modifications that mark cell memory seem to be of special importance for the cells involved in the complex processes of learning and memory.

Adult humans harbor at least as many microbial cells as eukaryotic ones. The largest compartment of this diverse microbial population, the gut microbiota, encompasses the collection of bacteria, archaea, viruses, and eukaryotic organisms that populate the gastrointestinal tract, and represents a complex and dynamic ecosystem that has been increasingly implicated in health and disease. The gut microbiota carries ∼100-to-150-times more genes than the human genome and is intimately involved in development, homeostasis, and disease. Of the several microbial metabolites that have been studied, short-chain fatty acids emerge as a group of molecules that shape gene expression in several types of eukaryotic cells by multiple mechanisms, which include DNA methylation changes, histone post-translational modifications, and microRNA-mediated gene silencing. Butyric acid, one of the most extensively studied short-chain fatty acids, reaches higher concentrations in the colonic lumen, where it provides a source of energy for healthy colonocytes, and its concentrations decrease towards the bottom of the colonic crypts, where stem cells reside. The lower butyric acid concentration in the colonic crypts allows undifferentiated cells, such as stem cells, to progress through the cell cycle, pointing towards the importance of the crypts in providing them with a protective niche. In cancerous colonocytes, which metabolize relatively little butyric acid and mostly rely on glycolysis, butyric acid preferentially acts as a histone deacetylase inhibitor, leading to decreased cell proliferation and increased apoptosis. A better understanding of the interface between the gut microbiota metabolites and epigenetic changes in eukaryotic cells promises to unravel in more detail processes that occur physiologically and as part of disease, help develop novel biomarkers, and identify new therapeutic modalities.

Epigenetics is the field of science that deals with the study of changes in gene function that do not involve changes in DNA sequence and are heritable while epigenetics inheritance is the process of transmission of epigenetic modifications to the next generation. It can be transient, intergenerational, or transgenerational. There are various epigenetic modifications involving mechanisms such as DNA methylation, histone modification, and noncoding RNA expression, all of which are inheritable. In this chapter, we summarize the information on epigenetic inheritance, its mechanism, inheritance studies on various organisms, factors affecting epigenetic modifications and their inheritance, and the role of epigenetic inheritance in the heritability of diseases.

CD8⁺ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8⁺ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8⁺ T-cell differentiation and the antitumor immune response. In a murine tumor-bearing model, an increased tumor size and decreased survival rate were observed in T-cell-specific Utx KO (Utx KO) mice compared with wild-type (WT) mice. The number of CD8⁺ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8⁺ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8⁺ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8⁺ T cells to tumor sites, was substantially decreased in Utx KO CD8⁺ T cells. These findings suggest that Utx promotes CD8⁺ T-cell-dependent antitumor immune responses partially through epigenetic regulation of the effector function.

Gene expression altering epigenomic modifications such as DNA methylation, histone modification, and chromosome remodeling is crucial to regulating many biological processes. Several lifestyle factors, such as diet and natural, bioactive food compounds, such as vitamins, modify epigenetic patterns. However, epigenetic dysregulation can increase the risk of many diseases, including cancer. Various studies have provided supporting and contrasting evidence on the relationship between vitamins and cancer risk. Though there is a gap in knowledge about whether dietary vitamins can induce epigenetic modifications in the context of colorectal cancer (CRC), the possibility of using them as epidrugs for CRC treatment is being explored. This is promising because such studies might be informative about the most effective way to use vitamins in combination with DNA methyltransferase inhibitors and other approved therapies to prevent and treat CRC. This review summarizes the available epidemiological and observational studies involving dietary, circulating levels, and supplementation of vitamins and their relationship with CRC risk. Additionally, using available in vitro, in vivo, and human observational studies, the role of vitamins as potential epigenetic modifiers in CRC is discussed. This review is focused on the action of vitamins as modifiers of DNA methylation because aberrant DNA methylation, together with genetic alterations, can induce the initiation and progression of CRC. Although this review presents some studies with promising results, studies with better study designs are necessary. A thorough understanding of the underlying molecular mechanisms of vitamin-mediated epigenetic regulation of CRC genes can help identify effective therapeutic targets for CRC prevention and treatment.

While in the past technology has mostly been utilized to store information about the structural configuration of proteins and molecules for research and medical purposes, Artificial Intelligence is nowadays able to learn from the existing data how to predict and model properties and interactions, revealing important knowledge about complex biological processes, such as aging. Modern technologies, moreover, can rely on a broader set of information, including those derived from the next-generation sequencing (e.g., proteomics, lipidomics, and other omics), to understand the interactions between human body and the external environment. This is especially relevant as external factors have been shown to have a key role in aging. As the field of computational systems biology keeps improving and new biomarkers of aging are being developed, artificial intelligence promises to become a major ally of aging research.

The genome is almost identical in all the cells of the body. However, the functions and morphologies of each cell are different, and the factors that determine them are the genes and proteins expressed in the cells. Over the past decades, studies on epigenetic information, such as DNA methylation, histone modifications, chromatin accessibility, and chromatin conformation have shown that these properties play a fundamental role in gene regulation. Furthermore, various diseases such as cancer have been found to be associated with epigenetic mechanisms. In this study, we summarized the biological properties of epigenetics and single-cell epigenomic profiling techniques, and discussed future challenges in the field of epigenetics.

Conrad Waddington's epigenetics landscape has provided a metaphorical framework for how cells progress from undifferentiated states to one of several discrete, distinct, differentiated cell fates. The understanding of epigenetics has evolved over time, with DNA methylation being the most studied epigenetic modification, followed by histone modifications and non-coding RNA. Cardiovascular diseases (CVD) are leading contributors to death worldwide, with the prevalence of CVDs increasing across the last couple of decades. Significant amount of resources being poured into researching key mechanisms and underpinnings of the various CVDs. These molecular studies looked at the genetics, epigenetics as well as the transcriptomics of various cardiovascular conditions, aiming to provide mechanistic insights. It has paved the way for therapeutics to be developed and in recent years, epi-drugs for the treatment of CVDs. This chapter aims to cover the various roles of epigenetics in the context of cardiovascular health and disease. The following will be examined in detail: the developments in basic experimental techniques used to study epigenetics, the role of epigenetics in various CVDs (hypertension, atrial fibrillation, atherosclerosis, and heart failure), and current advances in epi-therapeutics, providing a holistic view of the current concerted efforts in advancing the field of epigenetics in CVDs.

Exposure to environmental pollution and the increase in the incidence of multifactorial diseases in the population have become health problems for industrialized countries. In this context, the question of the health impact of exposure to these pollutants is not clearly identified in the low-dose range. This article looks at this problem using the example of preclinical studies of the effects of chronic low-dose exposure to uranium in rats. These studies demonstrate the value of molecular screening analyses (omics) and multimodal integrative approaches, of which the extreme sensitivity and breadth of observation spectrum make it possible to observe all the biological processes affected and the mechanisms of action triggered at the molecular level by exposure to low doses. They also show the value of these analytical approaches for finding diagnostic biomarkers or indicators of prognosis, which can be necessary to evaluate a risk. Finally, the results of these studies raise the question of the health risk caused by epigenomic deregulations occurring during critical developmental phases and their potential contribution to the development of chronic diseases that are metabolic in origin or to the development of certain cancer liable in the long term to affect the exposed adult and possibly its progeny.

The renewal of the natural resources is one of the most concerning aspects of modern farming. In animal production, there are many barriers breeders and researchers have to overcome to develop new practices to improve reproductive potential and hasten sexual maturation of the commercially viable species, while maintaining meat quality and sustainability. With the utilization of molecular biology techniques, there have been relevant advances in the knowledge of spermatogenesis, especially in mammals, resulting in new possibilities to control male fertility and the selection of desirable characteristics. Most of these discoveries have not been implemented in animal production. In this review, recent studies are highlighted on the molecular pathways involved in spermatogenesis in the context of animal production. There is also exploration of the interaction between environmental factors and spermatogenesis and how this knowledge may revolutionize animal production techniques. Furthermore, new insights are described about the inheritance of desired characteristics in mammals and there is a review of nefarious actions of pollutants, nutrition, and metabolism on reproductive potential in subsequent generations. Even though there are these advances in knowledge base, results from recent studies indicate there are previously unrecognized environmental effects on spermatogenesis. The molecular mechanisms underlying this interaction are not well understood. Research in spermatogenesis, therefore, remains pivotal as a pillar of animal production sustainability.

Clipping of the histone H3 N-terminal tail has been implicated in multiple fundamental biological processes for a growing list of eukaryotes. H3 clipping, serving as an irreversible process to permanently remove some post-translational modifications (PTMs), may lead to noticeable changes in chromatin dynamics or gene expression. The eukaryotic model organism Tetrahymena thermophila is among the first few eukaryotes that exhibits H3 clipping activity, wherein the first six amino acids of H3 are cleaved off during vegetative growth. Clipping only occurs in the transcriptionally silent micronucleus of the binucleated T. thermophila, thus offering a unique opportunity to reveal the role of H3 clipping in epigenetic regulation. However, the physiological functions of the truncated H3 and its protease(s) for clipping remain elusive. Here, we review the major findings of H3 clipping in T. thermophila and highlight its association with histone modifications and cell cycle regulation. We also summarize the functions and mechanisms of H3 clipping in other eukaryotes, focusing on the high diversity in terms of protease families and cleavage sites. Finally, we predict several protease candidates in T. thermophila and provide insights for future studies.

The online version contains supplementary material available at 10.1007/s42995-022-00151-0.

Epigenetics is a series of alterations regulating gene expression without disrupting the DNA sequence of bases. These regulatory mechanisms can result in embryogenesis, cellular differentiation, X-chromosome inactivation, and DNA-protein interactions. The main epigenetic mechanisms considered to play a major role in both health and disease are DNA methylation, histone modifications, and profiling of non-coding RNA. When the fragile balance between these simultaneously occurring phenomena is disrupted, the risk of pathology increases. Thus, the factors that determine proper epigenetic modeling are defined and those with disruptive influence are sought. Several such factors with proven negative effects have already been described. Diet and nutritional substances have recently been one of the most interesting targets of exploration for epigenetic modeling in disease states, including autoimmunity. The preventive role of proper nutrition and maintaining sufficient vitamin D concentration in maternal blood during pregnancy, as well as in the early years of life, is emphasized. Opportunities are also being investigated for affecting the course of the disease by exploring nutriepigenetics. The authors aim to review the literature presenting vitamin D as one of the important nutrients potentially modeling the course of disease in selected autoimmune disorders.