A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing health outcomes. Excess GR-activation in utero has been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type specific effects. To address this, we used an in vitro model of fetal human brain, induced pluripotent-stem-cell-derived cerebral organoids, and mapped GR-activation effects using single-cell transcriptomics across development. Interestingly, neurons showed targeted regulation of differentiation-and maturation-related transcripts, suggesting a delay of these processes upon GR-activation. Uniquely in neurons, differentially-expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This suggests that aberrant GR-

Schizophrenia (SCZ) is a devastating mental disorder that is characterized by distortions in thinking, perception, emotion, language, sense of self, and behavior. Epidemiological evidence suggests that subtle perturbations in early neurodevelopment increase later susceptibility for disease, which typically manifests in adolescence to early adulthood. Early perturbations are thought to be significantly mediated through incompletely understood genetic risk factors. The advent of induced pluripotent stem cell (iPSC) technology allows for the in vitro analysis of disease-relevant neuronal cell types from the early stages of human brain development. Since iPSCs capture each donor’s genotype, comparison between neuronal cells derived from healthy and diseased individuals can provide important insights into the molecular and cellular basis of SCZ. In this review, we discuss results from an increasing number of iPSC-based SCZ/control studies that highlight alterations in neuronal differentiation, maturation, and neurotransmission in addition to perturbed mitochondrial function and micro-RNA expression. In light of this remarkable progress, we consider also ongoing challenges from the field of iPSC-based disease modeling that call for further improvements on the generation and design of patient-specific iPSC studies to ultimately progress from basic studies on SCZ to tailored treatments.

Brain development is guided by the interactions between the genetic blueprint and the environment. Epigenetic mechanisms, especially DNA methylation, can mediate these interactions and may also trigger long-lasting adaptations in developmental programs that increase the risk of major depressive disorders (MDD) and schizophrenia (SCZ). Early life adversity is a major risk factor for MDD/SCZ and can trigger persistent genome-wide changes in DNA methylation at genes important to early, but also to mature, brain function, including neural proliferation, differentiation, and synaptic plasticity, among others. Moreover, genetic variations controlling dynamic DNA methylation in early life are thought to influence later epigenomic changes in SCZ. This finding corroborates the high genetic load and a neurodevelopmental origin of SCZ and shows that epigenetic responses to the environment are, at least in part, genetically controlled. Interestingly, genetic variants influencing DNA methylation are also enriched in risk variants from genome-wide association studies (GWAS) on SCZ supporting a role in neurodevelopment. Overall, epigenomic responses to early life adversity appear to be controlled to different degrees by genetics in MDD/SCZ, even though the potential reversibility of epigenomic processes may offer new hope for timely therapeutic interventions in MDD/SCZ.

Bipolar disease (BD) is one of the major public health burdens worldwide and more people are affected every year. Comprehensive genetic studies have associated thousands of single nucleotide polymorphisms (SNPs) with BD risk; yet, very little is known about their functional roles. Induced pluripotent stem cells (iPSCs) are powerful tools for investigating the relationship between genotype and phenotype in disease-relevant tissues and cell types. Neural cells generated from BD-specific iPSCs are thought to capture associated genetic risk factors, known and unknown, and to allow the analysis of their effects on cellular and molecular phenotypes. Interestingly, an increasing number of studies on BD-derived iPSCs report distinct alterations in neural patterning, postmitotic calcium signaling, and neuronal excitability. Importantly, these alterations are partly normalized by lithium, a first line treatment in BD. In light of these exciting findings, we discuss current challenges to the field of iPSC-based disease modelling and future steps to be taken in order to fully exploit the potential of this approach for the investigation of BD and the development of new therapies.

Polycomb Group (PcG) proteins are best-known for maintaining repressive or active chromatin states that are passed on across multiple cell divisions, and thus sustain long-term memory of gene expression. PcG proteins engage different, partly gene-and/or stage-specific, mechanisms to mediate spatiotemporal gene expression during central nervous system development. In the course of this, PcG proteins bind to various cis-regulatory sequences (e.g., promoters, enhancers or silencers) and coordinate, as well the interactions between distantly separated genomic regions to control chromatin function at different scales ranging from compaction of the linear chromatin to the formation of topological hubs. Recent findings show that PcG proteins are involved in switch-like changes in gene expression states of selected neural genes during the transition from multipotent to differentiating cells, and then to mature neurons. Beyond neurodevelopment, PcG proteins sustain mature neuronal function and viability, and prevent progressive neurodegeneration in mice. In support of this view, neuropathological findings from human neurodegenerative diseases point to altered PcG functions. Overall, improved insight into the multiplicity of PcG functions may advance our understanding of human neurodegenerative diseases and ultimately pave the way to new therapies.

Glucocorticoids are important for proper organ maturation1. Increased exposure to these hormones during pregnancy, as a result of commonly prescribed synthetic glucocorticoids such as dexamethasone in preterm births2, has been associated with lasting effects on the offspring, including on neurodevelopment and neuropsychiatric disease risk3. While the consequences of glucocorticoid excess in term and especially adult brain have been extensively studied, mainly in rodents4, studies on their effects during early human cortical development are absent. Here we use human cerebral organoids and mice to study cell-type specific effects of glucocorticoids on neurogenic processes. We show that glucocorticoid administration during neurogenesis alters the cellular architecture of the developing cortex by increasing a specific type of gyrencephalic species-enriched basal progenitors that co-express PAX6 and EOMES. This effect is mediated via the glucocorticoid-responsive transcription factor ZBTB16 as shown with overexpression, genetic knock-down and reporter assays experiments in organoids and embryonic mouse models and leads to increased production of deep-layer neurons. A phenome-wide mendelian randomization analysis of a genetic intronic enhancer variant that moderates glucocorticoid-induced ZBTB16 levels, as shown with enhancer assays and enhancer-editing in organoids, reveals potential causal relationships with increased educational attainment as well as neuroimaging phenotypes in adults. In this study we provide a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that potentially explains postnatal phenotypes and may be used to refine treatment guidelines.

Alzheimer's disease (AD) is a fatal neurodegenerative disease which is on the rise worldwide. Despite a wealth of information, genetic factors contributing to the emergence of AD still remain incompletely understood. Sporadic AD is polygenetic in nature and is associated with various environmental risks. Epigenetic mechanisms are well-recognized in the mediation of gene environment interactions, and analysis of epigenetic changes at the genome scale can offer new insights into the relationship between brain epigenomes and AD. In fact, recent epigenome-wide association studies (EWAS) indicate that changes in DNA methylation are an early event preceding clinical manifestation and are tightly associated with AD neuropathology. Further, candidate genes from EWAS interact with those from genome-wide association studies (GWAS) that can undergo epigenetic changes in their upstream gene regulatory elements. Functionally, AD-associated DNA methylation changes partially influence transcription of candidate genes involved in pathways relevant to AD. The timing of epigenomic changes in AD together with the genes affected indicate a critical role, however, further mechanistic insight is required to corroborate this hypothesis. In this respect, recent advances in neuronal reprogramming of patient-derived cells combined with new genome-editing techniques offer unprecedented opportunities to dissect the functional and mechanistic role of epigenomic changes in AD.