Pharmacogenetics, the study of how interindividual genetic differences affect drug response, does not explain all observed heritable variance in drug response. Epigenetic mechanisms, such as DNA methylation, and histone acetylation may account for some of the unexplained variances. Epigenetic mechanisms modulate gene expression and can be suitable drug targets and can impact the action of nonepigenetic drugs. Pharmacoepigenetics is the field that studies the relationship between epigenetic variability and drug response. Much of this research focuses on compounds targeting epigenetic mechanisms, called epigenetic drugs, which are used to treat cancers, immune disorders, and other diseases. Several studies also suggest an epigenetic role in classical drug response; however, we know little about this area. The amount of information correlating epigenetic biomarkers to molecular datasets has recently expanded due to technological advances, and novel computational approaches have emerged to better identify and predict epigenetic interactions. We propose that the relationship between epigenetics and classical drug response may be examined using data already available by (1) finding regions of epigenetic variance, (2) pinpointing key epigenetic biomarkers within these regions, and (3) mapping these biomarkers to a drug-response phenotype. This approach expands on existing knowledge to generate putative pharmacoepigenetic relationships, which can be tested experimentally. Epigenetic modifications are involved in disease and drug response. Therefore, understanding how epigenetic drivers impact the response to classical drugs is important for improving drug design and administration to better treat disease.

The prenatal environment may program health and disease susceptibility via epigenetic mechanisms. We evaluated associations of maternal trimester-specific intake of micronutrients with global DNA methylation (%5mC) and 5-hydroxymethylation (%5hmC) at birth in cord blood and tested for persistence into childhood. We quantified global %5mC and %5hmC in cord blood cells (n = 434) and in leukocytes collected in early (n = 108) and mid-childhood (n = 390) from children in Project Viva, a pre-birth cohort from Boston, MA. Validated food frequency questionnaires estimated maternal first- and second-trimester intakes of vitamin B2, vitamin B6, vitamin B12, folate, betaine, choline, methionine, iron, and zinc. Mean (SD) cord blood %5mC and %5hmC was 5.62% (2.04) and 0.25% (0.15), respectively. Each μg increase in first-trimester B12 intake was associated with 0.002 lower %5hmC in cord blood (95% CI: −0.005, −0.0003), and this association persisted in early childhood (β = −0.007; 95% CI: −0.01, −0.001) but not mid-childhood. Second-trimester iron (mg) was associated with 0.01 lower %5mC (95% CI: −0.02, −0.002) and 0.001 lower %5hmC (95% CI: −0.01, −0.00001) in cord blood only. Increased second-trimester zinc (mg) intake was associated with 0.003 greater %5hmC in early childhood (β = 0.003; 95% CI: 0.0004, 0.006). Second-trimester folate was positively associated with %5hmC in early childhood only (β = 0.08, 95% CI: 0.003, 0.16). Associations did not survive multiple testing adjustment; future replication is needed. Trimester-specific nutrients may impact various sensitive windows of epigenetic programming some with lasting effects in childhood. Further research is needed to understand the role of gene-specific epigenetic changes and how global DNA methylation measures relate to child health.

Despite the importance of secondary dormancy for plant life cycle timing and survival, there is insufficient knowledge about the (epigenetic) regulation of this trait at the molecular level. Our aim was to determine the role of (epi)genetic processes in the regulation of secondary seed dormancy using natural genotypes of the widely distributed Capsella bursa-pastoris. Seeds of nine ecotypes were exposed to control conditions or histone deacetylase inhibitors [trichostatin A (TSA), valproic acid] during imbibition to study the effects of hyper-acetylation on secondary seed dormancy induction and germination. Valproic acid increased secondary dormancy and both compounds caused a delay of t50 for germination (radicle emergence) but not of t50 for testa rupture, demonstrating that they reduced speed of germination. Transcriptome analysis of one accession exposed to valproic acid versus water showed mixed regulation of ABA, negative regulation of GAs, BRs and auxins, as well as up-regulation of SNL genes, which might explain the observed delay in germination and increase in secondary dormancy. In addition, two accessions differing in secondary dormancy depth (deep vs non-deep) were studied using RNA-seq to reveal the potential regulatory processes underlying this trait. Phytohormone synthesis or signalling was generally up-regulated for ABA (e.g. NCED6, NCED2, ABCG40, ABI3) and down-regulated for GAs (GA20ox1, GA20ox2, bHLH93), ethylene (ACO1, ERF4-LIKE, ERF105, ERF109-LIKE), BRs (BIA1, CYP708A2-LIKE, probable WRKY46, BAK1, BEN1, BES1, BRI1) and auxin (GH3.3, GH3.6, ABCB19, TGG4, AUX1, PIN6, WAT1). Epigenetic candidates for variation in secondary dormancy depth include SNL genes, histone deacetylases and associated genes (HDA14, HDA6-LIKE, HDA-LIKE, ING2, JMJ30), as well as sequences linked to histone acetyltransferases (bZIP11, ARID1A-LIKE), or to gene silencing through histone methylation (SUVH7, SUVH9, CLF). Together, these results show that phytohormones and epigenetic regulation play an important role in controlling differences in secondary dormancy depth between accessions.

The role of early life nutrition's impact on relevant health outcomes across the lifespan laid the foundation for the field titled the developmental origins of health and disease. Studies in this area initially concentrated on nutrition and the risk of adverse cardio-metabolic and cancer outcomes. More recently the role of nutrition in early brain development and the subsequent influence of later mental health has become more evident. Scientific breakthroughs have elucidated two mechanisms behind long-term nutrient effects on the brain, including the existence of critical periods for certain nutrients during brain development and nutrient-driven epigenetic modifications of chromatin. While multiple nutrients and nutritional conditions have the potential to modify brain development, iron can serve as a paradigm to understand both mechanisms. New horizons in nutritional medicine include leveraging the mechanistic knowledge of nutrient–brain interactions to propose novel nutritional approaches that protect the developing brain through better timing of nutrient delivery and potential reversal of negative epigenetic marks. The main challenge in the field is detecting whether a change in nutritional status truly affects the brain's development and performance in human subjects. To that end, a strong case can be made to develop and utilise bioindicators of a nutrient's effect on the developing brain instead of relying exclusively on biomarkers of the nutrient's status.

The multifactorial etiology of pediatric cancer is poorly understood. Environmental factors occurring during embryogenesis can disrupt epigenetic signaling, resulting in several diseases after birth, including cancer. Associations between assisted reproductive technologies (ART), such as in vitro fertilization (IVF), and birth defects, imprinting disorders and other perinatal adverse events have been reported. IVF can result in methylation changes in the offspring, and a link with pediatric cancer has been suggested. In this study, we investigated the peripheral blood methylomes of 11 patients conceived by IVF who developed cancer in childhood. Methylation data of patients and paired sex/aged controls were obtained using the Infinium MethylationEPIC Kit (Illumina). We identified 25 differentially methylated regions (DMRs), 17 of them hypermethylated, and 8 hypomethylated in patients. The most significant DMR was a hypermethylated genomic segment located in the promoter region of LHX6, a transcription factor involved in the forebrain development and interneuron migration during embryogenesis. An additional control group was included to verify the LHX6 methylation status in children with similar cancers who were not conceived by ART. The higher LHX6 methylation levels in IVF patients compared to both control groups (healthy children and children conceived naturally who developed similar pediatric cancers), suggested that hypermethylation at the LHX6 promoter could be due to the IVF process and not secondary to the cancer itself. Further studies are required to evaluate this association and the potential role of LHX6 promoter hypermethylation for tumorigenesis.

Molecular psychiatry research needs a deeper characterization of emotional and cognitive neural underpinnings, along with a broader recognition of trauma-related circuitries and their involvement in shared pathological endophenotypes. One such endophenotype is unbalanced approach avoidance conflict (AAC), a highly recurrent trait of psychopathology. A translationally validated rodent model of AAC is the elevated plus maze (EPM) test, recently shown to be pharmacologically controlled in human and rodents via homologous neural substrates. Thanks to this test, we identified the involvement of the epigenetic enzyme LSD1 as a molecular restrainer of anxiety. We identified LSD1 aberrant regulation within the hippocampus of suicidal victims, suggesting its broad functional involvement in maladaptive behaviors. Interestingly, thanks to the parallel employment of rodent models, we evaluated a stress-related LSD1 homeostatic regulation that transiently limits memory formation-instrumental gene expression in the hippocampus upon trauma. Our work shed new light on epigenetic processes devoted to trauma resiliency through a negative regulation of anxiety plasticity.

Several observational studies investigated risk factors for suicide attempts/completed suicides in older age with contrasting evidence from ongoing population-based research. The risk factors most associated to suicide attempts than other variables were: depressive disorders, methods employed to self-harm (particularly poisoning), and psychotropic drug utilization followed by psychological factors and disability. Moreover, male sex, violent methods to self-harm, any psychiatric disorder (depression, anxiety and bipolar disorders), a poor medical condition, stressors/bereavement, and living alone appeared to be more significant for predicting completed suicides in late life. There is growing evidence of a role of environmental exposures in the pathogenesis and epigenetics of suicidal behavior in older age. Little is known about the possible relationship between suicidal ideation in older age and its biopsychosocial predictors, although psychiatric disorders (among which late-life depression, LLD), play a fundamental role. LLD, distinguished as late-onset depression (LOD) and early-onset depression (EOD). Suicidal ideators accounted for 2.32% of subjects, were female, smokers and obese affected by multimorbidity. After adjusting for age, gender, education and social dysfunction, suicidal ideation was associated to LLD (EOD>LOD:OR:21.71, 95% CI:9.22-51.14). In the full random forest model, asthma was the most important contributor to suicidal ideation. Among biomarkers, interleukin (IL)-6 followed by tumor necrosis factor (TNF)-a, Apolipoprotein E e4 allele-carriers, C-reactive protein contributed most to suicidal ideation. Although EOD is a strong determinant of suicidal ideation, other non-psychiatric factors, i.e., serum inflammation biomarkers, APOE e4 allele, and multimorbidity, should be taken into account when evaluating a suicidal ideation phenotype in older age.

Preterm birth (PTB) is one of the leading causes of deaths in infants under the age of five. Known risk factors of PTB include genetic factors, lifestyle choices or infection. Identification of omic biomarkers associated with PTB could aid clinical management of women at high risk of early labour and thereby reduce neonatal morbidity. This systematic literature review aimed to identify and summarise maternal omic and multi-omic (genomics, transcriptomics, proteomics and metabolites) biomarker studies of PTB. Original research articles were retrieved from three databases: PubMed, Web of Science and Science Direct, using specified search terms for each omic discipline. PTB studies investigating genomics, transcriptomics, proteomics or metabolomics biomarkers prior to onset of labour were included. Data were collected and reviewed independently. Pathway analyses were completed on the biomarkers from non-targeted omic studies using Reactome pathway analysis tool. A total of 149 omic studies were identified; most of the literature investigated proteomic biomarkers. Pathway analysis identified several cellular processes associated with the omic biomarkers reported in the literature. Study heterogeneity was observed across the research articles, including the use of different gestation cut-offs to define PTB. Infection/inflammatory biomarkers were identified across majority of papers using a range of targeted and non-targeted approaches.

There is an accumulating data that shows relation between childhood adversity and vulnerability to chronic diseases as well as epigenetic influences that in turn give rise to these diseases. Asthma is one of the chronic diseases that is influenced from genetic regulation of the inflammatory biomolecules and therefore the hypothesis in this research was childhood adversity might have caused epigenetic differentiation in the asthma-related genes in the population who had childhood trauma. To test this hypothesis, the literature was systematically reviewed to extract epigenetically modified gene data of the adults who had childhood adversity, and affected genes were further evaluated for their association with asthma. PRISMA guidelines were adopted and PubMed and Google Scholar were included in the searched databases, to evaluate epigenetic modifications in asthma-related genes of physically, emotionally or sexually abused children. After retrieving a total of 5245 articles, 36 of them were included in the study. Several genes and pathways that may contribute to pathogenesis of asthma development, increased inflammation, or response to asthma treatment were found epigenetically affected by childhood traumas. Childhood adversity, causing epigenetic changes in DNA, may lead to asthma development or influence the course of the disease and therefore should be taken into account for the prolonged health consequences.

A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research.