New Model Helps Unravel Complex Psychiatric Disorders Such As Autism and Schizophrenia

La ricerca si concentra sulla mappatura dei componenti cis-regolatori nei neuroni umani che possono essere collegati alla genetica dei disturbi psichiatrici.

Il modello delle cellule staminali del Monte Sinai potrebbe essere in grado di far luce sulla complessa biologia alla base di alcuni disturbi psichiatrici.

Per mappare le varianti del rischio di malattia nei neuroni umani, i ricercatori della Icahn School of Medicine del Monte Sinai hanno utilizzato un modello unico di cellule staminali. Questo lavoro può aiutare a far luce sui meccanismi biologici alla base di malattie neuropsichiatriche come l'autismo e la schizofrenia.

Nan Yang

Nan Yang, Ph.D., assistente professore di neuroscienze. Credito: Sistema sanitario del Monte Sinai

Il modello cellulare etichettato in laboratorio del gruppo, recentemente pubblicato su Cell Reports, è stato creato per facilitare la comprensione da parte dei futuri ricercatori dei meccanismi patologici che coinvolgono gli studi di associazione sull'intero genoma (GWAS) che caratterizzano diversi alleli di rischio (varianti genetiche comuni che conferiscono rischio) per i disturbi psichiatrici . Questo studio potrebbe aiutare a sviluppare metodi diagnostici migliori per rilevare i problemi mentali anni prima che un paziente sviluppi i sintomi.

La ricerca si concentra sull'identificazione di elementi cis-regolatori nei neuroni umani che potrebbero essere collegati all'ereditabilità dei disturbi psichiatrici. Gli elementi normativi cis, che includono potenziatori e promotori, non sono codificanti[{" attribute="">DNA regions that control the expression of genes and are essential parts of the genetic regulatory network. A considerable enrichment of common variants in the cis-regulatory elements, including those linked to bipolar disorder, schizophrenia, and autism spectrum disorder, has been found in previous genetic investigations.

“While common risk variants can shed light on the underlying molecular mechanism, identifying causal variants remains challenging for scientists,” says Nan Yang, Ph.D., Assistant Professor of Neuroscience at the Icahn School of Medicine of Mount Sinai, and senior author of the study. “That’s because cis-regulatory elements, particularly the enhancers, vary across cell types and activity states. Typically, researchers can only use postmortem brain samples where the neurons are no longer active. As a result, they are likely to miss enhancers that only respond to stimulation. Our approach is to map cis-regulatory elements in human neurons derived from pluripotent stem cells. That allows us to replicate neurons in the human brain that can be affected by different types of neuropsychiatric disease, and conduct mechanistic studies of human genetic variants that are inaccessible from other types of human samples.”

In recent years, GWAS have identified hundreds of gene regions associated with psychiatric disease, though understanding disease pathophysiology has been elusive. The functional genomics approach Dr. Yang and her team developed uses stem cell models that can help resolve the impact of patient-specific variants across cell types, genetic backgrounds, and environmental conditions. This unique approach effectively lays a foundation to translate risk variants to genes, genes to pathways, and pathways to circuits that reveal the synergistic relationship between disease risk factors within and between the cell types in the brain.

“Our research attempts to decode and transfer highly complex genetic insights into medically actionable information,” says Dr. Yang, who is a member of the Black Family Stem Cell Institute, The Friedman Brain Institute, and The Ronald M. Loeb Center for Alzheimer’s Disease within the Mount Sinai Health System. “That means improving our diagnostic capabilities, predicting clinical trajectories, and identifying presymptomatic points of therapeutic intervention for psychiatric disorders.”

By characterizing cell-type specific and activity-regulated gene expression patterns in human cell-derived neurons, Dr. Yang believes her team’s study can greatly benefit the research community. “Our data can guide choosing relevant cell types of experimental conditions to further elucidate molecular mechanisms of disease across the genome,” she points out. “And that could lead to the development of biomarkers that might detect neuropsychiatric disorders years before they manifest themselves in patients, while there is still time to delay or possibly prevent them.”

Reference: “Mapping cis-regulatory elements in human neurons links psychiatric disease heritability and activity-regulated transcriptional programs” by Carlos Sanchez-Priego, Ruiqi Hu, Linda L. Boshans, Matthew Lalli, Justyna A. Janas, Sarah E. Williams, Zhiqiang Dong and Nan Yang, 31 May 2022, Cell Reports.
DOI: 10.1016/j.celrep.2022.110877

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