Epigenetic Effects Research Articles

Maternal Hypertension Aggravates Vascular Dysfunction After Injury in Male Adult Offspring Through Transgenerational Transmission of N6-Methyladenosine.

Whether maternal hypertension contributes to the enhanced susceptibility to vascular remodeling in adult offspring through epigenetic mechanisms remains unclear. We aimed to address this gap in the literature using a transgenerational mouse model. Gestational hypertension was induced in pregnant mice using chronic angiotensin II infusion. Blood pressure was monitored using the tail-cuff method. Two months post-delivery, an N6-methyladenosine epitranscriptomic microarray analysis was performed on the carotid arteries of second-generation mice. A unilateral carotid artery injury model was used to study the postinjury vascular response in vivo. Furthermore, carotid ultrasonography, immunohistochemistry, and molecular biological parameters were assessed in adult offspring. Exposure to maternal hypertension decreased the birth weight of live pups and increased the fetal death rate. Compared with normal offspring, adult offspring with hypertension had wire-induced injury that led to greater vascular remodeling, which was associated with aggravated inflammation imbalance, fibrosis, and oxidative stress. In addition, aberrant N6-methyladenosine methylation, increased N6-methyladenosine levels, and increased METTL3 (methyltransferase-like 3) expression were detected in the vessels of offspring with hypertension. Maternal METTL3 deficiency increased the birth weight of live pups with hypertension, improved vascular dysfunction, and alleviated vascular inflammation in adult offspring with hypertension after injury. Maternal hypertension can induce transgenerational transmission of enhanced susceptibility to vascular remodeling, and the possible underlying mechanism is associated with altered METTL3-mediated N6-methyladenosine methylation. Therefore, this study reveals the role of epigenetic effects across generations and provides new insights into vascular remodeling causes.

<!--StartFragment--> The Delos Mutation: Interdisciplinary Entanglements between Biology and Architecture 1963 – 1975 <!--EndFragment-->

This article traces the interdisciplinary entanglement between biology and architecture at The Delos Symposion, a series of annual week-long architecture and urbanism symposia convened by architect and planner Constantinos Doxiadis (1913–1975), ten of which took place on a cruise ship in the Mediterranean Sea between 1963 and 1972. These Delos symposia stand out as a pioneering interdisciplinary initiative and a unique think-tank for future-oriented developments in both architectural theory and biology, united by a common interest in cybernetics. Biologist Conrad Hal Waddington (1905–1975), who attended all ten Delos gatherings, was a forerunner of such new developments in biology; at Delos he discussed how his ground-breaking theory of epigenetics would change how designers would build, plan, and conceptualize buildings and cities. This article is a critical study of how Waddington’s epigenetic theory mutated into architecture and urban theory. First, I discuss Doxiadis’ holistic urban theory of ekistics in relation to Waddington’s epigenetic theory by focusing on the notion of open-endedness in the two theories. The article then argues that the discussions on planning and design at Delos affected Waddington’s thinking, changing a structural belief in planning into a post-structural disbelief in certitude. The interdisciplinary Delos discussions about planning and architecture triggered the scientist to turn toward aesthetics and ethical epistemology as a response to an uncertain future — a transmutation that impelled ethical and epistemological developments that still resonate in critical discourses in the humanities.

Antimicrobial activity and cytotoxic and epigenetic effects of tannic acid-loaded chitosan nanoparticles

Tannic acid (TA) is a potent antitumor agent, but its low bioavailability and absorption limit its use. In this study, it was loaded into chitosan-based nanoparticles (Chi-NPs) to overcome these limitations and to improve its antimicrobial and anticancer activities. TA-loaded Chi-NPs (Chi-TA-NPs) were synthesized using the ionic gelation method and physicochemically characterized by FE-SEM, FTIR, XRD, PDI, DLS, and zeta potential analysis. Additionally, the antimicrobial activity of Chi-TA-NPs against two G+ bacterial strains, two G− bacterial strains, and a fungal strain (Candida albicans) was investigated using the microbroth dilution method. MTT assay was used to examine the cytotoxic effects of Chi-TA-NPs on HepG2 cells. The expression of DNA methyltransferase 1 (DNMT1), DNMT3A, and DNMT3B was examined in HepG2 cells using RT-qPCR. The amount of 5-methylcytosine in the HepG2 cell-derived genomic DNA was measured using ELISA. FE-SEM micrographs showed the loading of TA into the chitosan-based formulation. The peaks detected in the XRD and FTIR analyses confirmed the formation of the Chi-TA-NPs. The PDI value (0.247 ± 0.03), size (567.0 ± 25.84 nm), and zeta potential (17.0 ± 5.86 mV) confirmed the relative stability of Chi-TA-NPs. A constant release profile in line with the Korsmeyer-Peppas model was detected for Chi-TA-NPs, such that approximately 44% of TA was released after 300 min. In addition, Chi-TA-NPs exhibited effective antimicrobial activity against the studied microbial strains, as manifested by MIC values ranging from 250 to 1000 µg/mL. Chi-TA-NPs induced cytotoxicity in liver tumor cell line, with an IC50 value of 500 µg/mL. Furthermore, Chi-TA-NPs considerably decreased the expression of DNMT1 (2.52-fold; p = 0.01), DNMT3A (2.96-fold; p = 0.004), and DNMT3B (2.94-fold; p < 0.0001). However, 5-methylcytosine levels in HepG2 cells were unaffected by Chi-TA-NPs treatment (p = 0.62). Finally, the antimicrobial, cytotoxic, and epigenetic effects of Chi-TA-NPs were more pronounced than those of free TA and the unloaded Chi-NPs. In conclusion, Chi-TA-NPs exhibit promising potential for reducing microbial growth and promoting cytotoxicity in liver cancer cells.

Potential regulatory mechanism and clinical significance of synaptotagmin binding cytoplasmic RNA interacting protein in colorectal cancer.

Colorectal cancer (CRC) causes many deaths worldwide. Synaptotagmin binding cytoplasmic RNA interacting protein (SYNCRIP) is an RNA-binding protein that plays an important role in multiple cancers by epigenetically targeting some genes. Our study will examine the expression, potential effect, biological function and clinical value of SYNCRIP in CRC. To examine the expression, potential effect, biological function and clinical value of SYNCRIP in CRC. The expression of SYNCRIP was examined by immunohistochemistry arrays and high-throughput data. The effect of SYNCRIP gene in CRC cell growth was evaluated by CRISPR-Cas9 technology. The target genes of SYNCRIP were calculated using various algorithms, and the molecular mechanism of SYNCRIP in CRC was explored by mutation analysis and pathway analysis. The clinical value of SYNCRIP in prognosis and radiotherapy was revealed via evidence-based medicine methods. The protein and mRNA levels of SYNCRIP were both highly expressed in CRC samples compared to nontumorous tissue based on 330 immunohistochemistry arrays and 3640 CRC samples. Cells grew more slowly in eleven CRC cell lines after knocking out the SYNCRIP gene. SYNCRIP could epigenetically target genes to promote the occurrence and development of CRC by boosting the cell cycle and affecting the tumor microenvironment. In addition, CRC patients with high SYNCRIP expression are more sensitive to radiotherapy. SYNCRIP is upregulated in CRC, and highly expressed SYNCRIP can accelerate CRC cell division by exerting its epigenetic regulatory effects. In addition, SYNCRIP is expected to become a potential biomarker to predict the effect of radiotherapy.

Multi-strain probiotic administration decreases necrotizing enterocolitis severity and alters the epigenetic profile in mice.

Probiotic administration may decrease the incidence of necrotizing enterocolitis (NEC) through mechanisms that are largely unknown. We investigated the effects of probiotics on intestinal epigenetics and assessed their effects on intestinal inflammation and motility using both ileum-predominant and combined ileo-colitis mouse NEC models. C57BL/6 J mice were gavage-fed a multi-strain probiotic from postnatal days 3-11, consisting of B. infantis, B. lactis, and S. thermophilus. From p8, mice were exposed to ileo-colitis NEC involving formula containing NEC bacteria and 0.5% DSS. DNA methylation was measured using the Infinium Methylation Assay. Gastrointestinal motility was assessed by 70 Kd FITC-dextran transit time. Probiotic colonization was measured in probiotic-fed mice by qPCR. Probiotic administration caused significant changes in the small intestine's epigenetic signature, a reduction in NEC severity, and improved intestinal motility. The effects of probiotics were more pronounced in the ileo-colitis NEC model. These findings shed light on the role of probiotics in two clinically relevant models of NEC, add additional insights into their underlying mechanism of action, and reveal unanticipated epigenetic modifications to the intestinal mucosa after their use. These findings shed light on the role of multi-strain probiotics in two clinically relevant animal models of NEC, and add additional insights into their underlying mechanism of action This study provides a new, clinically relevant model for the study of NEC including administration of 0.5% DSS, to include ileal dominant and ileo-colonic dominant phenotypes of the disease. These results reveal that clinically relevant strains of probiotic bacteria can exert epigenetic effects on the small intestine in mice, and can attenuate the epigenetic changes induced by NEC.

The impact of a polyphenol-rich supplement on epigenetic and cellular markers of immune age: a pilot clinical study.

ClinicalTrials.gov, Identifier: NCT05234203.

Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer.

Germline BRCA1 mutation carriers face a high breast cancer risk; however, the underlying mechanisms for this risk are not completely understood. Using a new genetically engineered mouse model of germline Brca1 heterozygosity, we demonstrate that early tumor onset in a Brca1 heterozygous background cannot be fully explained by the conventional 'two-hit' hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1 heterozygous state. Single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1 heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells. Transcription factor analyses identify loss of ELF5 and gain of AP-1 sites in these epigenetically primed regions; in vivo experiments further implicate AP-1 and Wnt10a as strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1 haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies.

Epigenetic Effects of Natural Products in Inflammatory Diseases: Recent Findings.

Inflammation is an essential step for the etiology of multiple diseases. Clinically, due to the limitations of current drugs for the treatment of inflammatory diseases, such as serious side effects and expensive costs, it is urgent to explore novel mechanisms and medicines. Natural products have received extensive attention recently because of their multi-component and multi-target characteristics. Epigenetic modifications are crucial pathophysiological targets for developing innovative therapies for pharmacological interventions. Investigations examining how natural products improving inflammation through epigenetic modifications are emerging. This review state that natural products relieve inflammation via regulating the gene transcription levels through chromosome structure regulated by histone acetylation levels and the addition or deletion of methyl groups on DNA duplex. They could also exert anti-inflammatory effects by modulating the proteins in typical inflammatory signaling pathways by ubiquitin-related degradation and the effect of glycolysis derived free glycosyls. Studies on epigenetic modifications have the potential to facilitate the development of natural products as therapeutic agents. Future research directed at better understanding of how natural products modulate inflammatory processes through less studied epigenetic modifications including neddylation, SUMOylation, palmitoylation and lactylation, may provide new implications. Meanwhile, higher quality preclinical studies and more powerful clinical evidence are still needed to firmly establish the clinical efficacy of the natural products. Trial Registration: ClinicalTrials.gov Identifier: NCT01764204; ClinicalTrials.gov Identifier: NCT05845931; ClinicalTrials.gov Identifier: NCT04657926; ClinicalTrials.gov Identifier: NCT02330276.

Epigenetic training of human bronchial epithelium cells by repeated rhinovirus infections.

Humans are subjected to various environmental stressors (bacteria, viruses, pollution) throughout life. As such, an inherent relationship exists between the effect of these exposures with age. The impact of these environmental stressors can manifest through DNA methylation (DNAm). However, whether these epigenetic effects selectively target genes, pathways, and biological regulatory mechanisms remains unclear. Due to the frequency of human rhinovirus (HRV) infections throughout life (particularly in early development), we propose the use of HRV under controlled conditions can model the effect of multiple exposures to environmental stressors. We generated a prediction model by combining transcriptome and DNAm datasets from human epithelial cells after repeated HRV infections. We applied a novel experimental statistical design and method to systematically explore the multifaceted experimental space (number of infections, multiplicity of infections and duration). Our model included 35 samples, each characterized by the three parameters defining their infection status. Trainable genes were defined by a consistent linear directionality in DNAm and gene expression changes with successive infections. We identified 77 trainable genes which could be further explored in future studies. The identified methylation sites were tracked within a pediatric cohort to determine the relative changes in candidate-trained sites with disease status and age. Repeated viral infections induce an immune training response in bronchial epithelial cells. Training-sensitive DNAm sites indicate alternate divergent associations in asthma compared to healthy individuals. Our novel model presents a robust tool for identifying trainable genes, providing a foundation for future studies.

Effects of Vitamin D Supplementation and a Cafeteria Diet on Various Parameters in the Next Generation of Rats with Metabolic Syndrome.

Metabolic Syndrome (MetS) is an increasingly widespread public health problem worldwide. MetS is associated with a cafeteria diet characterized by high fat and high simple carbohydrates. A cafeteria diet significantly affects serum glucose, creatine, urea, triglyceride, cholesterol and MetS parameters such as ALT, AST and ALP. Due to its epigenetic effects, vitamin D is important in controlling MetS parameters and minimizing MetS findings in subsequent generations. In this study, the effect of weekly 0.3 mL (1.000 IU/week) vitamin D intervention on MetS parameters was investigated in parental rats developing high-fructose MetS and their offspring. Offspring of MetS rats receiving and not receiving vitamin D supplementation were divided into four different groups and exposed to a cafeteria diet and vitamin D supplementation for eight weeks. It was shown that parental rats in the intervention group had lower serum urea, glucose, creatine, total cholesterol, ALP, AST and ALT levels (p < 0.05). Serum urea, glucose, creatine, ALT, AST, ALP, triglyceride, total cholesterol levels and body weights were lower and HDL levels were higher in the offspring (p < 0.05). However, initial serum ALT and AST values were higher in the offspring of MetS parent rats receiving vitamin D supplementation and in the offspring of rats not receiving supplementation than in the offspring of supplemented parents. In conclusion, it was found that vitamin D supplementation improved MetS parameters in parent rats, positively affected MetS parameters in offspring rats despite an inadequate diet, and positively affected some MetS parameters by affecting epigenetic pathways in offspring born to MetS mothers.

The epigenetic effects of glucocorticoids, sex hormones and vitamin D as steroidal hormones in rheumatic musculoskeletal diseases.

Chronic rheumatological diseases are multifactorial conditions in which both the neuroendocrine hormone pathway, including cortisol, sex hormones and active vitamin D3 (calcitriol), all deriving from cholesterol, and the epigenetic modifications that they cause play an important role. In fact, epigenetics modulates the function of the DNA of immune cells, through three main mechanisms: DNA methylation, modifications to the histones that make up chromatin and production of non-coding RNAs (microRNA - miRNA). In this narrative review, the main data regarding the epigenetic modifications induced by cortisol, 17β-oestradiol, progesterone, testosterone and calcitriol on immune cells were collected, discussing how these can interfere in the predisposition and course of chronic rheumatological diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis). An ever-increasing number of miRNAs have been identified, which are produced by neuroendocrine hormones and can influence the inflammatory-fibrotic response at various levels. Concerning the involvements of the neuro-endocrine-immunology within the pathophysiology of rheumatic diseases, the epigenetic effects induced by steroid hormones must be taken into consideration to evaluate their impact on the progression of the single condition and even inside the single patient.

Toxicity as process: tracing a new epigenetic regime of im/perceptibility in environmental toxicology

ABSTRACT Science and Technology Studies (STS) research has paid considerable attention to how toxicology produces knowledge on toxicity and how this knowledge has changed. For example, modern toxicological approaches of dose–response and threshold levels and genetic/genomic approaches for tracing exposure-induced DNA damage have been found to yield specific notions of toxicity. However, some of the toxicants’ latent exposure effects have remained invisible with these two established epistemic perspectives. To tackle this issue, environmental toxicologists have recently turned to environmental epigenetics, offering a promising biomolecular perspective to better understand the role of latent exposure effects on health. Analysing environmental toxicology literature on epigenetics and interviews with key researchers demonstrates how an epigenetic perspective yields a novel notion of toxicity as process. This temporal emphasis foregrounds the idea that bodies are not just exposed to toxicants but dynamically respond to the exposures they experience. In particular, environmental toxicologists draw on a specific combination of an epigenetic theory of toxicity and new but compatible methods and technologies, which establish a new epistemic understanding of toxicity. Characterising these developments as a Regime of Im/Perceptibility shows how novel regimes can emerge in both difference and continuity with prior regimes such as modern and genetic/genomic toxicology. The case study on epigenetic research in environmental toxicology adds to STS scholarship on epistemic developments in scientific fields by illuminating how a new epistemic perspective is successfully adopted while co-existing with established regimes of knowledge production in a given field.

Epigenetic regulation of myogenesis by vitamin C.

The micronutrient vitamin C is essential for the maintenance of skeletal muscle health and homeostasis. The pro-myogenic effects of vitamin C have long been attributed to its role as a general antioxidant agent, as well as its role in collagen matrix synthesis and carnitine biosynthesis. Here, we show that vitamin C also functions as an epigenetic compound, facilitating chromatin landscape transitions during myogenesis through its activity as an enzymatic cofactor for histone H3 and DNA demethylation. Utilizing C2C12 myoblast cells to investigate the epigenetic effects of vitamin C on myogenesis, we observe that treatment of cells with vitamin C decreases global H3K9 methylation and increases 5-hmC levels. Furthermore, vitamin C treatment enhances myoblast marker gene expression and myotube formation during differentiation. We identify KDM7A as a histone lysine demethylase markedly upregulated during myogenesis. Accordingly, knockdown of Kdm7a prevents the pro-myogenic effects of vitamin C. Chromatin immunoprecipitation analysis showed that KDM7A occupies the promoter region of the myogenic transcription factor MyoD1 where it facilitates histone demethylation. We also confirm that the methylcytosine dioxygenases TET1 and TET2 are required for myogenic differentiation and that their loss blunts stimulation of myogenesis by vitamin C. In conclusion, our data suggest that an epigenetic mode of action plays a major role in the myogenic effects of vitamin C.

MicroRNA Biogenesis, Gene Regulation Mechanisms, and Availability in Foods.

MicroRNAs (miRNAs) are small, non-coding RNAs that control gene expression by degrading or repressing mRNA translation into proteins. Research recently suggested that food-derived miRNAs are bioavailable and may be absorbed in the gastrointestinal tract (GIT). Since these small RNAs may reach the circulation and organs, possible interactions with host genes will lead to epigenetic effects that alter metabolism. Therefore, from a precision nutrition standpoint, exogenous miRNAs may be essential in modulating health status. This review summarizes the process of miRNA biogenesis, the post-translational mechanisms of gene regulation, and their bioavailability in animal- and plant-derived foods.

Strategies to Target Chemoradiotherapy Resistance in Small Cell Lung Cancer.

Background: Small cell lung cancer (SCLC) is a lethal form of lung cancer with few treatment options and a high rate of relapse. While SCLC is initially sensitive to first-line DNA-damaging chemo- and radiotherapy, relapse disease is almost universally therapy-resistant. As a result, there has been interest in understanding the mechanisms of therapeutic resistance in this disease. Conclusions: Progress has been made in elucidating these mechanisms, particularly as they relate to the DNA damage response and SCLC differentiation and transformation, leading to many clinical trials investigating new therapies and combinations. Yet there remain many gaps in our understanding, such as the effect of epigenetics or the tumor microenvironment on treatment response, and no single mechanism has been found to be ubiquitous, suggesting a significant heterogeneity in the mechanisms of acquired resistance. Nevertheless, the advancement of techniques in the laboratory and the clinic will improve our ability to study this disease, especially in patient populations, and identify methods to surmount therapeutic resistance.

Synergistic Effect of Some Molecular Biomarkers in The Development of Preeclampsia and Abortion in Pregnant Women Suffer from Toxoplasmosis

The current study summarized the effect of toxoplasmosis, which is caused by parasitic infection with protozoan known as Toxoplasma gondii, on pregnant women who suffer from repeated miscarriages, especially in the first trimester of pregnancy, this research documented the reduction of sex hormones values in healthy pregnant women, association with down ROP16 regulation(T.gondii-I virulence factor). While the average of the same parameters was increased in pregnant women who suffered from toxoplasmosis, which in turn led to inhibition of the transcription factor NFKB in parasite`s infected women, and inhibition of the patient's immune response. On the other hand, both of ROP16 and NFKB genes play a critical role in an increase of miR146 transcription, it consider a significant factor that activate epigenetic effect perhaps play role in reducing of host's immune system. At the end the placental cell signaling pathway was modified and increased atrophy of placental trophoblast with association of serious complications led at the end to emergence of early abortion.

Yiqi Yangxue formula inhibits cartilage degeneration in knee osteoarthritis by regulating LncRNA-UFC1/miR-34a/MMP-13 axis

Ethnopharmacological relevanceKnee osteoarthritis (KOA) is a prevalent and disabling clinical condition affecting joint structures worldwide. The Yiqi Yangxue formula (YQYXF) is frequently prescribed in clinical settings for the treatment of KOA. Existing research has primarily focused on alterations in drug metabolism, with limited investigation into the epigenetic effects of YQYXF, particularly in relation to non-coding RNA. Aim of the studyExploring the effects of YQYXF on critical factors of long chain non-coding RNA UFC1/miR-34a/matrix metalloproteinase-13 (MMP-13) axis and their interrelationships. MethodsUHPLC-QE-MS technology was used to identify the YQYXF ingredients in rat serum. KEGG and GO analysis were performed on the targets of blood components acting on KOA using a database. Simultaneously, a protein interaction network was constructed using target proteins and metabolites to identify the core components and key pathways of YQYXF. The KOA rat model was established using an improved Hulth method. SPF SD rats were randomly divided into normal group, sham surgery group, model group, celecoxib capsules group (18 mg/kg), YQYXF low, medium and high dose groups (4.6 g/kg, 9.2 g/kg, 18.4 g/kg). Observe the synovial and cartilage tissues of rats using pathological methods. RT-PCR was used to detect the levels of UFC1, miR-34a, and MMP-13 in cartilage. Immunohistochemistry was used to detect the levels of MMP-13 and ADAMTS-5 in cartilage. ELISA method was used to detect the levels of MMP-13 and ADAMTS-5 in serum. In addition, we further validated the regulation of crucial factor expression levels of UFC1/miR-34a/MMP-13 axis in rat chondrocytes and degenerative chondrocytes of KOA patients by YQYXF, providing a basis for its treatment of KOA. ResultsThe compounds that YQYXF enters the bloodstream mainly contain flavonoids and phenylpropanoid compounds. The core components that act on OA include quercetin, fisetin, and demethylweldelolactone. The main target pathways are the IL-17 signaling pathway, lipid and atherosclerosis, cellular sensitivity, inflammatory mediator regulation of TRP channels, TNF signaling pathway, relaxin signaling pathway and C-type lectin receptor signaling pathway. YQYXF inhibited the expression of miR-34a and MMP-13 mRNA, and reduced the protein levels of MMP-13 and ADAMTS-5. In vitro studies have confirmed that 20% YQYXF serum promoted UFC1 and reduce miR-34a levels. In addition, miR-34a in sh-UFC1+10% YQYXF serum and sh-UFC1+20% YQYXF serum groups significantly decreased compared to the sh-UFC1 group. ConclusionThe anti-KOA cartilage degeneration effect of YQYXF might be related to inhibiting cell apoptosis and promoting cell proliferation, which regulated the lncRNA-UFC1/miR-34a/MMP-13 axis.

PET Imaging of the Serotonin 1A Receptor in Major Depressive Disorder: Hierarchical Multivariate Analysis of [11C]WAY100635 Overcomes Outcome Measure Discrepancies

Abstract The serotonin 1A receptor has been linked to both the pathophysiology of major depressive disorder (MDD) and the antidepressant action of serotonin reuptake inhibitors. Most PET studies of the serotonin 1A receptor in MDD used the receptor antagonist radioligand, [carbonyl-11C]WAY100635; however the interpretation of the combined results has been contentious owing to reports of higher or lower binding in MDD with different outcome measures. The reasons for these divergent results originate from several sources, including properties of the radiotracer itself, which complicate its quantification and interpretation; as well as from previously reported differences between MDD and healthy volunteers in both reference tissue binding and plasma free fraction, which are typically assumed not to differ. Recently, we have developed two novel hierarchical multivariate methods which we validated for the quantification and analysis of [11C]WAY100635, which show better accuracy and inferential efficiency compared to standard analysis approaches. Importantly, these new methods should theoretically be more resilient to many of the factors thought to have caused the discrepancies observed in previous studies. We sought to apply these methods in the largest [11C]WAY100635 sample to date, consisting of 160 individuals, including 103 MDD patients, of whom 50 were not-recently-medicated and 53 were antidepressant-exposed, as well as 57 healthy volunteers. While the outcome measure discrepancies were substantial using conventional univariate analysis, our multivariate analysis techniques instead yielded highly consistent results across PET outcome measures and across pharmacokinetic models, with all approaches showing higher serotonin 1A autoreceptor binding potential in the raphe nuclei of not-recently-medicated MDD patients relative to both healthy volunteers and antidepressant-exposed MDD patients. Moreover, with the additional precision of estimates afforded by this approach, we can show that while binding is also higher in projection areas in this group, these group differences are approximately half of those in the raphe nuclei, which are statistically distinguishable from one another. These results are consistent with the biological role of the serotonin 1A autoreceptor in the raphe nuclei in regulating serotonin neuron firing and release, and with preclinical and clinical evidence of deficient serotonin activity in MDD due to over expression of autoreceptors resulting from genetic and/or epigenetic effects. These results are also consistent with downregulation of autoreceptors as a mechanism of action of selective serotonin reuptake inhibitors. In summary, the results using multivariate analysis approaches therefore demonstrate both face and convergent validity, and may serve to provide a resolution and consensus interpretation for the disparate results of previous studies examining the serotonin 1A receptor in MDD.

Integrated multi-omics reveals contrasting epigenetic patterns in leaf and root morphogenesis in Aegilops speltoides

Aegilops speltoides, the closest ancestor of the wheat B subgenome, has been well studied genomically. However, the epigenetic landscape of Ae. speltoides and the effects of epigenetics on its growth and development remain poorly understood. Here, we present a comprehensive multi-omics atlas of leaves and roots in Ae. speltoides, encompassing transcriptome, DNA methylation, histone modifications, and small RNA profiling. Divergent DNA methylation levels were detected between leaves and roots, and were associated with differences in accumulated 24-nt siRNAs. DNA methylation changes in promoters and gene bodies showed strong connections with altered expression between leaves and roots. Transcriptional regulatory networks (TRN) reconstructed between leaves and roots were driven by tissue-specific TF families. DNA methylation and histone modification act together as switches that shape root and leaf morphogenesis by modulating the binding of tissue-specific TFs to their target genes. The TRNs in leaves and roots reshaped during wheat polyploidization were associated with alterations in epigenetic modifications. Collectively, these results not only shed light on the critical contribution of epigenetic regulation in the morphogenesis of leaves and roots in Ae. speltoides but also provide new insights for future investigations into the complex interplay of genetic and epigenetic factors in the developmental biology of common wheat.

Epigenetic effects of exercise on improving the adverse placental environment associated with maternal overweight and obesity

ObjectiveWe aimed to explore whether maternal exercise has epigenetic effects on improving the adverse placental environment associated with maternal overweight/obesity. MethodsBased on samples collected from an RCT cohort, differentially methylated genes and expressed protein-coding RNA were identified in the placentas of 16 women with overweight and obesity who did or did not participate in an exercise intervention using the Infinium HumanMethylation850 BeadChip array and RNA Sequencing-Based lncRNA Profiling. Potential target genes were further identified by integrating this information. Then, the target genes’ methylation and expression levels were verified, and correlation analysis was performed with placental oxidative stress markers and participants’ clinical metabolic parameters. ResultsA total of 3608 significant differentially methylated probes were detected. The CBR1 gene, which was previously identified as a possible antioxidant, was significantly hypomethylated at CPG site promoter regions in placentas from the exercise group, and CBR1 gene expression levels were significantly higher. CBR1 gene expression levels were negatively associated with DNA methylation levels. Furthermore, CBR1 gene expression levels were negatively correlated with MDA levels in both placenta and cord blood samples and insulin resistance levels in late pregnancy. Additionally, CBR1 methylation levels were positively correlated with fasting plasma glucose and insulin resistance levels in late pregnancy. ConclusionDNA methylation is involved in the ameliorating effect of exercise on the adverse placental environment associated with maternal overweight/obesity.