Researchers have applied a novel stem cell model to map disease risk variants in human neurons, which could help provide insights into the biological mechanisms that underlie neuropsychiatric disorders such as autism and schizophrenia.
The team’s in vitro cellular model, described in the issue of Cell Reports, is designed to enable future researchers to elucidate the disease mechanisms involving genome-wide association studies (GWAS) that characterize different risk alleles (common genetic variants conferring risk) for psychiatric disorders. This research could potentially lead to improved diagnostics for the detection of psychiatric disorders years before symptoms appear in patients.
The study focuses on mapping cis-regulatory elements in human neurons that can be linked to psychiatric disease heritability. Cis-regulatory elements, such as promoters and enhancers, are non-coding DNA sequences regulating gene expression and are thus vital components of the genetic regulatory network. Previous genetic studies have revealed a significant enrichment of common variants in the cis-regulatory elements, including those associated with autism spectrum disorder, schizophrenia, and bipolar disorder.
“While common risk variants can shed light on the underlying molecular mechanism, identifying causal variants remains challenging for scientists,” says the 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 Typically, researchers can only use postmortem brain samples where the neurons are no longer active.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 the team developed uses stem cell models that can help resolve the impact of patient-specific variants across cell types, genetic background, 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 the author. “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, the 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,” the author 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.”
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00652-0
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmapping-cis-regulatory&filter=22
Mapping regulatory elements in psychiatric disorders using a stem cell model
- 1,414 views
- Added
Latest News
Paranoia in the brain
By newseditor
Posted 16 Jun
In-vitro 3D culture of func…
By newseditor
Posted 15 Jun
Neural balance in the brain…
By newseditor
Posted 15 Jun
Antimalarial compounds reli…
By newseditor
Posted 15 Jun
3D imaging of whole human b…
By newseditor
Posted 14 Jun
Other Top Stories
Decoding mechanism of remembering – and forgetting
Read more
Why screen time can disrupt sleep
Read more
Regrowing hair on wounded skin
Read more
Metabolic reprogramming of energy pathway to protect against kidney…
Read more
Tiny mitochondria stimulate brain cell connections
Read more
Protocols
Bioengineered human colon o…
By newseditor
Posted 14 Jun
Development of an efficient…
By newseditor
Posted 12 Jun
A co-culture system of macr…
By newseditor
Posted 10 Jun
Analysis of 3D pathology sa…
By newseditor
Posted 08 Jun
Long-term expandable mouse…
By newseditor
Posted 07 Jun
Publications
NRG1-ErbB4 signaling in the…
By newseditor
Posted 15 Jun
HPV integration and cervica…
By newseditor
Posted 15 Jun
Cerebral tau pathology in c…
By newseditor
Posted 15 Jun
Cerebral tau pathology in c…
By newseditor
Posted 15 Jun
Synthetic biodegradable mic…
By newseditor
Posted 15 Jun
Presentations
Myelin plasticity in the ve…
By newseditor
Posted 10 Jun
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar