DNA Methylation Changes Research Articles

Impaired energy expenditure following exposure to either DDT or DDE in mice may be mediated by DNA methylation changes in brown adipose.

The insecticide dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite, dichlorodiphenyldichloroethylene (DDE), have been associated with increased adiposity and obesity in multiple generations of rodents and humans. These lipophilic pollutants accumulate in adipose tissue and appear to decrease energy expenditure through the impairment of thermogenesis in brown adipose tissue (BAT). We hypothesized that impaired thermogenesis is due to persistent epigenetic modifications of BAT. To address this, we exposed C57BL/6 J mice to DDT or DDE from gestational day (GD) 11.5 to postnatal day (PND) 5, evaluated longitudinal body temperature, and performed reduced representation bisulfite sequencing and RNA sequencing of BAT from infant and adult offspring. Exposure to DDT or DDE reduced core body temperature in adult mice, and differential methylation at the pathway and gene level was persistent from infancy to adulthood. Furthermore, thermogenesis and biological pathways essential for thermogenic function, such as oxidative phosphorylation and mechanistic target of rapamycin kinase (mTOR) signaling, were enriched with differential methylation and RNA transcription in adult mice exposed to DDT or DDE. PAZ6 human brown preadipocytes were differentiated in the presence of DDT or DDE to understand the brown adipocyte-autonomous effect of these pollutants. In vitro exposure led to limited changes in RNA expression; however, mitochondrial membrane potential was decreased in vitro with 0.1 µM and 1 µM doses of DDT or DDE. These results demonstrate that concentrations of DDT and DDE relevant to human exposure have a significant effect on thermogenesis, the transcriptome, and DNA methylome of mouse BAT and the mitochondrial function of human brown adipocytes.

The DNA methyltransferase DMAP1 is required for tissue maintenance and planarian regeneration

The precise regulation of transcription is required for embryonic development, adult tissue turnover, and regeneration. Epigenetic modifications play a crucial role in orchestrating and regulating the transcription of genes. These modifications are important in the transition of pluripotent stem cells and their progeny. Methylation, a key epigenetic modification, influences gene expression through changes in DNA methylation. Work in different organisms has shown that the DNA methyltransferase-1-associated protein (DMAP1) may associate with other molecules to repress transcription through DNA methylation. Thus, DMAP1 is a versatile protein implicated in a myriad of events, including pluripotency maintenance, DNA damage repair, and tumor suppression. While DMAP1 has been extensively studied in vitro, its complex regulation in the context of the adult organism remains unclear. To gain insights into the possible roles of DMAP1 at the organismal level, we used planarian flatworms that possess remarkable regenerative capabilities driven by pluripotent stem cells called neoblast. Our findings demonstrate the evolutionary conservation of DMAP1 in the planarian Schmidtea mediterranea. Functional disruption of DMAP1 through RNA interference revealed its critical role in tissue maintenance, neoblast differentiation, and regeneration in S. mediterranea. Moreover, our analysis unveiled a novel function for DMAP1 in regulating cell death in response to DNA damage and influencing the expression of axial polarity markers. Our findings provide a simplified paradigm for studying DMAP1's function in adult tissues.

Gastroenteropancreatic neuroendocrine tumors: Epigenetic landscape and clinical implications

Neuroendocrine tumors (NETs) are a rare, heterogenous group of neoplasms arising from cells of the neuroendocrine system. Amongst solid tumor malignancies, NETs are notable for overall genetic stability and recent data supports the notion that epigenetic changes may drive NET pathogenesis. In this review, major epigenetic mechanisms of NET pathogenesis are reviewed, including changes in DNA methylation, histone modification, chromatin remodeling, and microRNA. Prognostic implications of the above are discussed, as well as the expanding diagnostic utility of epigenetic markers in NETs. Lastly, preclinical and clinical evaluations of epigenetically targeted therapies in NETs and are reviewed, with a focus on future directions in therapeutic advancement.

Short-term PM2.5 exposure and DNA methylation changes of circadian rhythm genes: evidence from two experimental studies

Short-term PM2.5 exposure and DNA methylation changes of circadian rhythm genes: evidence from two experimental studies

An epigenome-wide study of selenium status and DNA methylation in the Strong Heart Study

BackgroundSelenium (Se) is an essential nutrient linked to adverse health endpoints at low and high levels. The mechanisms behind these relationships remain unclear and there is a need to further understand the epigenetic impacts of Se and their relationship to disease. We investigated the association between urinary Se levels and DNA methylation (DNAm) in the Strong Heart Study (SHS), a prospective study of cardiovascular disease (CVD) among American Indians adults. MethodsSelenium concentrations were measured in urine (collected in 1989–1991) using inductively coupled plasma mass spectrometry among 1,357 participants free of CVD and diabetes. DNAm in whole blood was measured cross-sectionally using the Illumina MethylationEPIC BeadChip (850 K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated cytosine-guanine dinucleotide (CpG) sites associated with urinary Se levels. ResultsThe mean (standard deviation) urinary Se concentration was 51.8 (25.1) μg/g creatinine. Across 788,368 CpG sites, five differentially methylated positions (DMP) (hypermethylated: cg00163554, cg18212762, cg11270656, and hypomethylated: cg25194720, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top hypermethylated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Elastic net models selected 425 hypo- and hyper-methylated DMPs associated with urinary Se, including three sites (cg00163554 [DIP2C], cg18212762 [MAP4K2], cg11270656 [GPIHBP1]) identified in linear regressions. ConclusionsUrinary Se was associated with minimal changes in DNAm in adults from American Indian communities across the Southwest and the Great Plains in the United States, suggesting that other mechanisms may be driving health impacts. Future analyses should explore other mechanistic biomarkers in human populations, determine these relationships prospectively, and investigate the potential role of differentially methylated sites with disease endpoints.

Advances in Melanoma: From Genetic Insights to Therapeutic Innovations.

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

Cadmium Exposure in Male Rats Results in Ovarian Granulosa Cell Apoptosis in Female Offspring and Paternal Genetic Effects.

The aim of this study was to investigate whether the damage to male offspring induced by cadmium (Cd) exposure during embryonic period leads to the apoptosis of ovarian granulosa cells (OGCs) in the next generation of female offspring, and whether this apoptosis in the offspring was due to paternal genetic effects. Pregnant Sprague-Dawley (SD) rats were exposed to CdCl2 (0, 0.5, 2.0, or 8.0 mg/kg) by gavage daily for 20 days to produce the filial 1 (F1) generation. F1 males were mated with newly purchased females to produce the F2 generation, and the F3 generation was generated in the same way. No apoptotic bodies were observed in the OGCs of either the F2 or F3 generation as shown by electron microscopy, and a reduced OGC apoptosis rate (detected by flow cytometry) was observed in F2 OGCs from the Cd-exposed group. Moreover, the mRNA (qRT-PCR) levels of Bax and Bcl-2 and the protein (western blotting) level of pro-caspase-8 increased in the F2 generation (p < 0.05). The expression of apoptosis-related miRNAs (qRT-PCR) and methylation of apoptosis-related genes (determined via bisulfite-sequencing PCR) in OGCs were further determined. Compared with those of the controls, the expression patterns of microRNAs (miRNAs) in the F2 offspring were different in the Cd-exposed group. The miR-92a-2-5p expression levels were decreased in both the F2 and F3 generations (p < 0.05), while the average methylation level of apoptosis-related genes did not change significantly (except for individual loci). In summary, this study showed that the paternal genetic intergenerational effect of male Cd exposure during embryonic period induced apoptosis of OGCs in the offspring was weakened, and the transgenerational effect disappeared; nevertheless, intergenerational and transgenerational changes in apoptosis-related genes, epigenetic modifications, DNA methylation, and miRNAs were observed, and may be important for understanding the homeostatic mechanisms of the body to alleviate the intergenerational transmission of Cd-induced damage.

DNA methylation correlates of chronological age in diverse human tissue types

BackgroundWhile the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types.ResultsHere, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project. We identified age-associated CpG sites (false discovery rate < 0.05) in 8 tissues (all except skeletal muscle, n = 47). This included 162,002 unique hypermethylated and 90,626 hypomethylated CpG sites across all tissue types, with 130,137 (80%) hypermethylated CpGs and 74,703 (82%) hypomethylated CpG sites observed in a single tissue type. While the majority of age-associated CpG sites appeared tissue-specific, the patterns of enrichment among genomic features, such as chromatin states and CpG islands, were similar across most tissues, suggesting common mechanisms underlying cellular aging. Consistent with previous findings, we observed that hypermethylated CpG sites are enriched in regions with repressed polycomb signatures and CpG islands, while hypomethylated CpG sites preferentially occurred in non-CpG islands and enhancers. To gain insights into the functional effects of age-related DNAm changes, we assessed the correlation between DNAm and local gene expression changes to identify age-related expression quantitative trait methylation (age-eQTMs). We identified several age-eQTMs present in multiple tissue-types, including in the CDKN2A, HENMT1, and VCWE regions.ConclusionOverall, our findings will aid future efforts to develop biomarkers of aging and understand mechanisms of aging in diverse human tissue types.

Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease

ObjectiveEpigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn’s disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as...

The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children’s Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.

Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

Long-term exposure to diesel exhaust particles induces concordant changes in DNA methylation and transcriptome in human adenocarcinoma alveolar basal epithelial cells

BackgroundDiesel exhaust particles (DEP), which contain hazardous compounds, are emitted during the combustion of diesel. As approximately one-third of the vehicles worldwide use diesel, there are growing concerns about the risks posed by DEP to human health. Long-term exposure to DEP is associated with airway hyperresponsiveness, pulmonary fibrosis, and inflammation; however, the molecular mechanisms behind the effects of DEP on the respiratory tract are poorly understood. Such mechanisms can be addressed by examining transcriptional and DNA methylation changes. Although several studies have focused on the effects of short-term DEP exposure on gene expression, research on the transcriptional effects and genome-wide DNA methylation changes caused by long-term DEP exposure is lacking. Hence, in this study, we investigated transcriptional and DNA methylation changes in human adenocarcinoma alveolar basal epithelial A549 cells caused by prolonged exposure to DEP and determined whether these changes are concordant.ResultsDNA methylation analysis using the Illumina Infinium MethylationEPIC BeadChips showed that the methylation levels of DEP-affected CpG sites in A549 cells changed in a dose-dependent manner; the extent of change increased with increasing dose reaching the statistical significance only in samples exposed to 30 µg/ml DEP. Four-week exposure to 30 µg/ml of DEP significantly induced DNA hypomethylation at 24,464 CpG sites, which were significantly enriched for DNase hypersensitive sites, genomic regions marked by H3K4me1 and H3K27ac, and several transcription factor binding sites. In contrast, 9,436 CpG sites with increased DNA methylation levels were significantly overrepresented in genomic regions marked by H3K27me3 as well as H3K4me1 and H3K27ac. In parallel, gene expression profiling by RNA sequencing demonstrated that long-term exposure to DEP altered the expression levels of 2,410 genes, enriching 16 gene sets including Xenobiotic metabolism, Inflammatory response, and Senescence. In silico analysis revealed that the expression levels of 854 genes correlated with the methylation levels of the DEP-affected cis-CpG sites.ConclusionsTo our knowledge, this is the first report of genome-wide transcriptional and DNA methylation changes and their associations in A549 cells following long-term exposure to DEP.

H2O2 priming: Biostimulation, drought tolerance and DNA methylation profile with intergenerational impact in tobacco plant

H2O2 is a promising priming agent due to its role in stress-response pathways and in the regulation of gene expression. Several studies have shown that H2O2 elicitation improves stress responses. However, information regarding of the intergenerational stress memory of the H2O2 priming is limited. Therefore, in this study, we evaluated the stress memory induced by H2O2 priming in tobacco plants by testing hydric stress phenotypic response and changes in DNA methylation in the parental priming line and in the next generation. Priming consisted of three foliar applications of 200 mM H2O2 every 5 days on 4-week-old plants. DNA methylation profiling was performed by Whole Genome Bisulphite Sequencing (WGBS). Hydric stress challenge consisted of three conditions: control (100 %), moderate (40–45 %) and severe (20–25 %) stress according to the available water field capacity. Plant response to the challenge was evaluated by morphological, biochemical, and molecular attributes. The results showed that H2O2 priming displayed a biostimulant effect on vegetative and root development, preventing growth stunting under drought conditions. Plant antioxidant activity was enhanced, as reflected by the decrease in endogenous H2O2. In drought conditions, proline content, CAT activity and gene expression of CHS, PIP1 and AQP1 genes were enhanced in the primed-plants (H), their progeny (F1), and the primed-progeny group (FH). DNA methylation profile revealed 795 differentially methylated cytosines (DmCs) in the progeny, with 89 associated with genes involved in cellular response to environmental stimuli. An interaction network highlighted stress response with flavoreductase enzyme as central interaction node, and in the second layer the Repressor of Silencing 1 (ROS1) gene. Thus, the findings suggest that H2O2 priming may induce intergenerational memory, presenting a potentially cost-effective strategy in stress management in agriculture.

Exploring prognostic DNA methylation genes in bladder cancer: a comprehensive analysis

The current study aimed to investigate the status of genes with prognostic DNA methylation sites in bladder cancer (BLCA). We obtained bulk transcriptome sequencing data, methylation data, and single-cell sequencing data of BLCA from public databases. Initially, Cox survival analysis was conducted for each methylation site, and genes with more than 10 methylation sites demonstrating prognostic significance were identified to form the BLCA prognostic methylation gene set. Subsequently, the intersection of marker genes associated with epithelial cells in single-cell sequencing analysis was obtained to acquire epithelial cell prognostic methylation genes. Utilizing ten machine learning algorithms for multiple combinations, we selected key genes (METRNL, SYT8, COL18A1, TAP1, MEST, AHNAK, RPP21, AKAP13, RNH1) based on the C-index from multiple validation sets. Single-factor and multi-factor Cox analyses were conducted incorporating clinical characteristics and model genes to identify independent prognostic factors (AHNAK, RNH1, TAP1, Age, and Stage) for constructing a Nomogram model, which was validated for its good diagnostic efficacy, prognostic prediction ability, and clinical decision-making benefits. Expression patterns of model genes varied among different clinical features. Seven immune cell infiltration prediction algorithms were used to assess the correlation between immune cell scores and Nomogram scores. Finally, drug sensitivity analysis of Nomogram model genes was conducted based on the CMap database, followed by molecular docking experiments. Our research offers a reference and theoretical basis for prognostic evaluation, drug selection, and understanding the impact of DNA methylation changes on the prognosis of BLCA.

Abstract Mo047: DNA METHYLATION AND TRANSCRIPTIONAL MARKERS OF MYOCARDIAL REVERSE REMODELING IN HF PATIENTS ON LVAD SUPPORT

Heart failure (HF) involves global genome modifications. Adverse structural and function remodeling that occurs in HF was initially considered to be irreversible. However, ~15% of HF patients on left ventricular assist device (LVAD) support show significant structural and functional reverse remodeling, distinguishing them as responders (R), while ~85% are non-responders (NR). DNA methylation and transcriptional changes that exert myocardial recovery is not well understood. To address this, we performed whole-genome bisulphite sequencing and RNA sequencing on paired myocardial biopsies from HF patients (n=84) before (pre-LVAD) and after LVAD unloading (post-LVAD). Post-LVAD samples showed activation of pathways including TGFβ signaling, PTEN and Fatty acid oxidation compared to pre. Integrating DNA methylation and transcriptomics data revealed hypomethylation (upregulation) of genes including Scaper, Frat1 and Magi1 and hypermethylation (downregulation) of Tpp3 and Icam. Overall, suggesting a unique ECM-specific stabilization pathway post-LVAD unloading. Segregating samples based on their response to LVAD unloading, pathways such as inflammation and fibrotic signaling were activated in postNR compared to preNR. Hypomethylation of Magi1 and hypermethylation of Tppp3 was observed in postNR suggesting cross-linking proteins and destabilization of microtubule formation as potential mechanisms of functional regression in NR. Conversly, postR showed activation of deubiquitination, oxidative phosphorylation and NLR signaling compared to preR. Finally, we observed integrin signaling, syndecan interaction, collagen degradation and wound healing pathways were activated in postR compared to postNR. Hypomethylation of actin cytoskeleton ( Myl12a ), microtubule/motor proteins ( Kif5b ) and tropomyosin ( Tpm3 ) were observed in postR, suggesting a plausible reverse remodeling mechanism mediated by ECM degradation and stabilization of myocardium in these patients. Western blot analysis also showed a trend towards an increase in collagen in postNR compared to postR (n=4, p=0.06). Finally, a mouse model of HF and recovery was used and pathways including ECM degradation and cardioprotective signaling were activated in mice that recovered from HF compared to mice that did not. Overall, our data suggests a unique ECM regulation pathway to contribute towards myocardial reverse remodeling in HF patients.

Alcohol Use Disorder–Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex

BackgroundAlcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms that underlie the development and progression of AUD remains limited. Here, we investigated AUD-associated DNA methylation changes within and across 2 addiction-relevant brain regions, the nucleus accumbens and dorsolateral prefrontal cortex. MethodsIllumina HumanMethylation EPIC array data from 119 decedents (61 cases, 58 controls) were analyzed using robust linear regression with adjustment for technical and biological variables. Associations were characterized using integrative analyses of public annotation data and published genetic and epigenetic studies. We also tested for brain region–shared and brain region–specific associations using mixed-effects modeling and assessed implications of these results using public gene expression data from human brain. ResultsAt a false discovery rate of ≤.05, we identified 105 unique AUD-associated CpGs (annotated to 120 genes) within and across brain regions. AUD-associated CpGs were enriched in histone marks that tag active promoters, and our strongest signals were specific to a single brain region. Some concordance was found between our results and those of earlier published alcohol use or dependence methylation studies. Of the 120 genes, 23 overlapped with previous genetic associations for substance use behaviors, some of which also overlapped with previous addiction-related methylation studies. ConclusionsOur findings identify AUD-associated methylation signals and provide evidence of overlap with previous genetic and methylation studies. These signals may constitute predisposing genetic differences or robust methylation changes associated with AUD, although more work is needed to further disentangle the mechanisms that underlie these associations and their implications for AUD.

Telehealth Parenting Program and Salivary Epigenetic Biomarkers in Preschool Children With Developmental Delay

Children with developmental delays are at a heightened risk of experiencing mental health challenges, and this risk is exacerbated among racially minoritized children who face disproportionate adversity. Understanding the impact of parenting interventions on biological markers associated with these risks is crucial for mitigating long-term health disparities. To examine the effect of 20 weeks of an internet-based parent-child interaction training (iPCIT) program on biomarkers associated with aging and chronic inflammation among preschoolers with developmental delay at 12-month follow-up. An observational secondary analysis of data from a randomized clinical trial conducted from March 17, 2016, to December 15, 2020, to assess changes in salivary DNA methylation (DNAm)-derived biomarkers following iPCIT intervention. Participants were recruited from 3 Part C early intervention sites in a large southeastern US city. Eligible participants included children recruited within 3 months of their third birthday who had a Child Behavior Checklist Externalizing Problems T score greater than 60 and provided saliva in at least 1 study wave. Data analysis was conducted May 2023 to April 2024. Participants received either iPCIT (a telehealth therapeutic intervention focused on enhancing the parent-child relationship and addressing behavioral challenges in young children) or referrals as usual. DNAm at the 12-month follow-up was assessed using the Infinium HumanMethylationEPIC Bead Chip Assay to derive biomarkers DunedinPACE, C-reactive protein (CRP), and interleukin-6 (IL-6). Analyses were intent-to-treat and used path analysis. A total of 71 children (mean [SD] age, 36.27 [0.61] months 51 male [71.8%] and 20 female [28.2%]) were analyzed, of whom 34 received iPCIT and 37 received referrals as usual. The iPCIT group had a slower pace of aging (β = 0.26; 95% CI, 0.06 to 0.50; P = .03) and less DNAm-derived CRP (β = 0.27; 95% CI, 0.05 to 0.49; P = .01) relative to the control condition at the 12-month follow-up. These associations remained significant after accounting for baseline DNAm score, child demographics, and symptom severity, and were independent of predicted buccal epithelial cell proportion for both DunedinPACE and CRP. There was no association with DNAm-derived IL-6 (β = 0.14; 95% CI, -0.08 to 0.36; P = .21). In this study of a parenting intervention, iPCIT, the association of intervention with decreased molecular markers of inflammation and biological aging suggests their potential to modify aspects of the biological embedding of stress. Understanding the systemic biological impact of such interventions offers insights into addressing health disparities and promoting resilience among vulnerable populations. ClinicalTrials.gov Identifier: NCT03260816.

Air pollution-linked epigenetic modifications in placental DNA: Prognostic potential for identifying future foetal anomalies

Prenatal exposure to air pollution is a significant risk factor for the mother and the developing foetus. The accumulation of pollutants in the placenta can cause a self-cascade loop of pro-inflammatory cytokine responses and DNA double-strand breaks. Previous research has shown that airborne particulate matter can damage the epigenome and disturb mitochondrial machinery, ultimately impairing placental function. Mitochondria are essential for preserving cellular homeostasis, energy metabolism, redox equilibrium, and epigenetic reprogramming. As these organelles are subtle targets of environmental exposures, any disruption in the signaling pathways can result in epigenomic instability, which can impact gene expression and mitochondrial function. This, in turn, can lead to changes in DNA methylation, post-translational histone modifications, and aberrant expression of microRNAs in proliferating trophoblast cells. The placenta has two distinct layers, cytotrophoblasts, and syncytiotrophoblasts, each with its mitochondria, which play important roles in preeclampsia, gestational diabetes, and overall health. Foetal nucleic acids enter maternal circulation during placental development because of necrotic, apoptotic, and inflammatory mechanisms. These nucleic acids reflect normal or abnormal ongoing cellular changes during prenatal foetal development. Detecting cell-free DNA in the bloodstream can be a biomarker for predicting negative pregnancy-related outcomes and recognizing abnormalities in foetal growth. Hence, a thorough understanding of how air pollution induces epigenetic variations within the placenta could offer crucial insights into underlying mechanisms and prolonged repercussions on foetal development and susceptibility in later stages of life.

Distinct saliva DNA methylation profiles in relation to treatment outcome in youth with posttraumatic stress disorder

In youth with posttraumatic stress disorder (PTSD) non-response rates after treatment are often high. Epigenetic mechanisms such as DNA methylation (DNAm) have previously been linked to PTSD pathogenesis, additionally DNAm may affect response to (psychological) therapies. Besides investigating the direct link between DNAm and treatment response, it might be helpful to investigate the link between DNAm and previously associated biological mechanisms with treatment outcome. Thereby gaining a deeper molecular understanding of how psychotherapy (reflecting a change in the environment) relates to epigenetic changes and the adaptability of individuals. To date, limited research is done in clinical samples and no studies have been conducted in youth. Therefore we conducted a study in a Dutch cohort of youth with and without PTSD (n = 87, age 8–18 years). We examined the cross-sectional and longitudinal changes of saliva-based genome-wide DNA methylation (DNAm) levels, and salivary cortisol secretion. The last might reflect possible abbreviations on the hypothalamic–pituitary– adrenal (HPA) axis. The HPA-axis is previously linked to DNAm and the development and recovery of PTSD. Youth were treated with 8 sessions of either Eye Movement Reprocessing Therapy (EMDR) or Trauma Focused Cognitive behavioral Therapy (TF-CBT). Our epigenome wide approach showed distinct methylation between treatment responders and non-responders on C18orf63 gene post-treatment. This genomic region is related to the PAX5 gene, involved in neurodevelopment and inflammation response. Additionally, our targeted approach indicated that there were longitudinal DNAm changes in successfully treated youth at the CRHR2 gene. Methylation at this gene was further correlated with cortisol secretion pre- and post-treatment. Awaiting replication, findings of this first study in youth point to molecular pathways involved in stress response and neuroplasticity to be associated with treatment response.

A stage-dependent seed defense response to explain efficient seed transmission of Xanthomonas citri pv. fuscans to common bean.

Although seed represents an important means of plant pathogen dispersion, the seed-pathogen dialogue remains largely unexplored. A multiomic approach was performed at different seed developmental stages of common bean (Phaseolus vulgaris L.) during asymptomatic colonization by Xanthomonas citri pv. fuscans (Xcf), At the early seed developmental stages, we observed high transcriptional changes both in seeds with bacterial recognition and defense signal transduction genes, and in bacteria with up-regulation of the bacterial type 3 secretion system. This high transcriptional activity of defense genes in Xcf-colonized seeds during maturation refutes the widely diffused assumption considering seeds as passive carriers of microbes. At later seed maturation stages, few transcriptome changes indicated a less intense molecular dialogue between the host and the pathogen, but marked by changes in DNA methylation of plant defense genes, in response to Xcf colonization. We showed examples of pathogen-specific DNA methylations in colonized seeds acting as plant defense silencing to repress plant immune response during the germination process. Finally, we propose a novel plant-pathogen interaction model, specific to the seed tissues, highlighting the existence of distinct phases during seed-pathogen interaction with seeds being actively interacting with colonizing pathogens, then both belligerents switching to more passive mode at later stages.