Cell Genomics, Год журнала: 2023, Номер 3(9), С. 100403 - 100403
Опубликована: Сен. 1, 2023
Zhang, Forrest et al combine allele-specific open chromatin (ASoC) mapping and CRISPR-editing to evaluate the functional impact of schizophrenia risk variants on human neuronal gene expression, synaptic development, function. In doing so, they uncover surprising non-additive effects between target genes regulated by same variant.
Язык: Английский
Gene, Год журнала: 2024, Номер 902, С. 148198 - 148198
Опубликована: Янв. 22, 2024
Neuronal development is a highly regulated mechanism that central to organismal function in animals. In humans, disruptions this process can lead range of neurodevelopmental phenotypes, including Schizophrenia (SCZ). SCZ has significant genetic component, whereby an individual with affected family member eight times more likely develop the disease than someone no history SCZ. By examining combination genomic, transcriptomic and epigenomic datasets, large-scale 'omics' studies aim delineate relationship between variation abnormal cellular activity brain. Herein, we provide brief overview some key omics methods currently being used research, RNA-seq, assay for transposase-accessible chromatin high-throughput sequencing (ATAC-seq) chromosome conformation capture (3C) approaches (e.g., Hi-C), as well single-cell/nuclei iterations these methods. We also discuss how techniques are employed further our understanding basis SCZ, identify associated molecular pathways, biomarkers, candidate drug targets.
Язык: Английский
Процитировано
5
Trends in Molecular Medicine, Год журнала: 2024, Номер 30(4), С. 380 - 391
Опубликована: Март 1, 2024
Feeding and eating disorders (FEDs) are heterogenous characterized by varying patterns of dysregulated weight. Genome-wide association studies (GWASs) clarifying their underlying biology genetic relationship to other psychiatric metabolic/anthropometric traits. Genetic research on anorexia nervosa (AN) has identified eight significant loci uncovered correlations implicating both risk factors. Careful explication these metabolic contributors may be key developing effective enduring treatments for devastating, life-altering, frequently lethal illnesses. We discuss clinical phenomenology, genomics, phenomics, intestinal microbiota, functional genomics propose a path that translates variants genes, genes pathways, pathways outcomes advance the science eventually treatment FEDs.
Язык: Английский
Процитировано
5
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown
Опубликована: Март 21, 2023
Genetic studies of schizophrenia (SCZ) reveal a complex polygenic risk architecture comprised hundreds variants, the majority which are common in population at-large and confer only modest increases disorder risk. Precisely how genetic variants with individually small predicted effects on gene expression combine to yield substantial clinical impacts aggregate is unclear. Towards this, we previously reported that combinatorial perturbation four SCZ genes ("eGenes", whose regulated by variants) resulted changes were not individual perturbations, being most non-additive among associated synaptic function Now, across fifteen eGenes, demonstrate greatest within groups functionally similar eGenes. Individual eGene perturbations downstream transcriptomic ("convergence"), while result smaller than summing ("sub-additive effects"). Unexpectedly, these convergent sub-additive overlap constitute large proportion genome-wide score, suggesting functional redundancy eGenes may be major mechanism underlying non-additivity. Single likewise fail predict magnitude or directionality cellular phenotypes resulting from perturbations. Overall, our results indicate cannot extrapolated experiments testing one at time must instead empirically measured. By unravelling interactions between it possible improve utility scores through more powerful prediction symptom onset, trajectory, treatment response, identify novel targets for therapeutic intervention.
Язык: Английский
Процитировано
7
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Авг. 24, 2024
Over a hundred risk genes underlie for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets increase ASD is unknown. To test hypothesis that cellular context impacts nature of convergence, here we apply pooled CRISPR approach target 29 loss-of-function in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level network-level analyses) demonstrate convergence greatest mature Convergent effects are dynamic, varying strength, composition, biological role between types, increasing with functional similarity examined, driven by cell-type-specific gene co-expression patterns. Stratification yield targeted drug predictions capable reversing gene-specific convergent signatures cells ASD-related behaviors zebrafish. Altogether, networks represent novel points individualized therapeutic intervention.
Язык: Английский
Процитировано
2
International Journal of Molecular Sciences, Год журнала: 2022, Номер 24(1), С. 241 - 241
Опубликована: Дек. 23, 2022
The study of diseases the central nervous system (CNS) at molecular level is challenging because complexity neural circuits and huge number specialized cell types. Moreover, genomic association studies have revealed complex genetic architecture schizophrenia other genetically determined mental disorders. Investigating such to decipher basis CNS pathologies requires use high-throughput models as cells their derivatives. time coming for technologies based on CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)/Cas systems manipulate multiple targets. CRISPR/Cas provide desired complexity, versatility, flexibility create novel tools capable both altering DNA sequence affecting its function higher levels information flow. make it possible find investigate intricate relationship between genotype phenotype neuronal cells. purpose this review discuss innovative CRISPR-based approaches studying mechanisms using cellular models.
Язык: Английский
Процитировано
4
Neuron, Год журнала: 2024, Номер unknown
Опубликована: Сен. 1, 2024
Язык: Английский
Процитировано
0
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown
Опубликована: Июль 19, 2023
ABSTRACT Common variants associated with schizophrenia are concentrated in non-coding regulatory sequences, but their precise target genes context-dependent and impacted by cell-type-specific three-dimensional spatial chromatin organization. Here, we map long-range chromosomal conformations isogenic human dopaminergic, GABAergic, glutamatergic neurons to track developmentally programmed shifts the activity of risk loci. Massive repressive compartmentalization, concomitant emergence hundreds neuron-specific multi-valent architectural stripes, occurs during neuronal differentiation, interconnected genetic loci through these structures differing biological roles from more proximal sequences conferring heritable risk. Chemically induced CRISPR-guided loop-engineering for gene SNAP91 distal BHLHE22 profoundly alters synaptic development functional activity. Our findings highlight large-scale reorganization at neurodevelopment establish a causal link between risk-associated gene-regulatory loop function.
Язык: Английский
Процитировано
1
Cell Genomics, Год журнала: 2023, Номер 3(9), С. 100403 - 100403
Опубликована: Сен. 1, 2023
Zhang, Forrest et al combine allele-specific open chromatin (ASoC) mapping and CRISPR-editing to evaluate the functional impact of schizophrenia risk variants on human neuronal gene expression, synaptic development, function. In doing so, they uncover surprising non-additive effects between target genes regulated by same variant.
Язык: Английский
Процитировано
0