Linking environmental factors and gene regulation.

A technique called mSTARR-seq sheds light on how DNA methylation may shape responses to external stimuli by altering the activity of sequences that control gene expression.

Human cortical neurogenesis is altered via glucocorticoid-mediated regulation of ZBTB16 expression.

Glucocorticoids are important for proper organ maturation, and their levels are tightly regulated during development. Here, we use human cerebral organoids and mice to study the cell-type-specific effects of glucocorticoids on neurogenesis. We show that glucocorticoids increase a specific type of basal progenitors (co-expressing PAX6 and EOMES) that has been shown to contribute to cortical expansion in gyrified species. This effect is mediated via the transcription factor ZBTB16 and leads to increased production of neurons. A phenome-wide Mendelian randomization analysis of an enhancer variant that moderates glucocorticoid-induced ZBTB16 levels reveals causal relationships with higher educational attainment and altered brain structure. The relationship with postnatal cognition is also supported by data from a prospective pregnancy cohort study. This work provides a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that relates to lasting postnatal phenotypes.

High-throughput screening of glucocorticoid-induced enhancer activity reveals mechanisms of stress-related psychiatric disorders.

Exposure to stressful life events increases the risk for psychiatric disorders. Mechanistic insight into the genetic factors moderating the impact of stress can increase our understanding of disease processes. Here, we test 3,662 single nucleotide polymorphisms (SNPs) from preselected expression quantitative trait loci in massively parallel reporter assays to identify genetic variants that modulate the activity of regulatory elements sensitive to glucocorticoids, important mediators of the stress response. Of the tested SNP sequences, 547 were located in glucocorticoid-responsive regulatory elements of which 233 showed allele-dependent activity. Transcripts regulated by these functional variants were enriched for those differentially expressed in psychiatric disorders in the postmortem brain. Phenome-wide Mendelian randomization analysis in 4,439 phenotypes revealed potentially causal associations specifically in neurobehavioral traits, including major depression and other psychiatric disorders. Finally, a functional gene score derived from these variants was significantly associated with differences in the physiological stress response, suggesting that these variants may alter disease risk by moderating the individual set point of the stress response.

Epigenetics and depression
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The risk for major depression is both genetically and environmentally determined. It has been proposed that epigenetic mechanisms could mediate the lasting increases in depression risk following exposure to adverse life events and provide a mechanistic framework within which genetic and environmental factors can be integrated. Epigenetics refers to processes affecting gene expression and translation that do not involve changes in the DNA sequence and include DNA methylation (DNAm) and microRNAs (miRNAs) as well as histone modifications. Here we review evidence for a role of epigenetics in the pathogenesis of depression from studies investigating DNAm, miRNAs, and histone modifications using different tissues and various experimental designs. From these studies, a model emerges where underlying genetic and environmental risk factors, and interactions between the two, could drive aberrant epigenetic mechanisms targeting stress response pathways, neuronal plasticity, and other behaviorally relevant pathways that have been implicated in major depression.
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El riesgo de presentar una depresión mayor está determinado genética y ambientalmente. Se ha planteado que los mecanismos epigenéticos podrían mediar los aumentos permanentes en el riesgo de depresión después de la exposición a acontecimientos adversos de la vida y proporcionar un marco mecanicista dentro del cual se puedan integrar los factores genéticos y ambientales. La epigenética abarca procesos que afectan la expresión y la traducción de genes que no implican cambios en la secuencia de ADN e incluyen metilación del ADN (DNAm), microARN (miARN), así como modificaciones de histonas. En este artículo se revisa la evidencia de la participación de la epigenética en la patogénesis de la depresión a partir de estudios que investigan las modificaciones de ADNm, miRNA e histonas mediante el empleo de diferentes tejidos y varios diseños experimentales. De estos estudios surge un modelo en el que los factores de riesgo genéticos y ambientales subyacentes, como las interacciones entre ambos, podrían conducir a mecanismos epigenéticos aberrantes con efectos en las vías de respuesta al estrés, en la plasticidad neuronal y en otras vías relevantes conductualmente que se han implicado en la depresión mayor.

Le risque de dépression majeure est déterminé à la fois génétiquement et par l'environnement. Des mécanismes épigénétiques pourraient relayer les augmentations durables de risque de dépression après une exposition aux événements de vie difficiles et fournir un cadre mécanistique dans lequel facteurs environnementaux et génétiques pourraient s'intégrer. L'épigénétique fait référence aux processus en rapport avec la traduction et l'expression des gènes sans modification de la séquence d'ADN : méthylation de l'ADN (ADNm), microARN (ARNmi) et modifications de l'histone. Dans cet article nous analysons des données d'études, dans différents tissus et à l'aide de schémas expérimentaux variés, sur l'ADNm, les ARNm et les modifications de l'histone comme preuves d'un rôle de l'épigénétique dans la pathogenèse de la dépression. De ces études émerge un modèle dans lequel des facteurs de risque génétiques et environnementaux, et les interactions entre les deux, pourraient susciter des mécanismes épigénétiques aberrants ciblant les voies de réponse au stress, la plasticité neuronale et d'autres voies comportementales impliquées dans la dépression majeure.

The temporal dynamics of chromosome instability in ovarian cancer cell lines and primary patient samples.

Epithelial ovarian cancer (EOC) is the most prevalent form of ovarian cancer and has the highest mortality rate. Novel insight into EOC is required to minimize the morbidity and mortality rates caused by recurrent, drug resistant disease. Although numerous studies have evaluated genome instability in EOC, none have addressed the putative role chromosome instability (CIN) has in disease progression and drug resistance. CIN is defined as an increase in the rate at which whole chromosomes or large parts thereof are gained or lost, and can only be evaluated using approaches capable of characterizing genetic or chromosomal heterogeneity within populations of cells. Although CIN is associated with numerous cancer types, its prevalence and dynamics in EOC is unknown. In this study, we assessed CIN within serial samples collected from the ascites of five EOC patients, and in two well-established ovarian cancer cell models of drug resistance (PEO1/4 and A2780s/cp). We quantified and compared CIN (as measured by nuclear areas and CIN Score (CS) values) within and between serial samples to glean insight into the association and dynamics of CIN within EOC, with a particular focus on resistant and recurrent disease. Using quantitative, single cell analyses we determined that CIN is associated with every sample evaluated and further show that many EOC samples exhibit a large degree of nuclear size and CS value heterogeneity. We also show that CIN is dynamic and generally increases within resistant disease. Finally, we show that both drug resistance models (PEO1/4 and A2780s/cp) exhibit heterogeneity, albeit to a much lesser extent. Surprisingly, the two cell line models exhibit remarkably similar levels of CIN, as the nuclear areas and CS values are largely overlapping between the corresponding paired lines. Accordingly, these data suggest CIN may represent a novel biomarker capable of monitoring changes in EOC progression associated with drug resistance.