Activity-Dependent Transcriptional Program in NGN2+ Neurons Enriched for Genetic Risk for Brain-Related Disorders.
Biol Psychiatry
; 95(2): 187-198, 2024 Jan 15.
Article
in En
| MEDLINE
| ID: mdl-37454787
ABSTRACT
BACKGROUND:
Converging evidence from large-scale genetic and postmortem studies highlights the role of aberrant neurotransmission and genetic regulation in brain-related disorders. However, identifying neuronal activity-regulated transcriptional programs in the human brain and understanding how changes contribute to disease remain challenging.METHODS:
To better understand how the activity-dependent regulome contributes to risk for brain-related disorders, we profiled the transcriptomic and epigenomic changes following neuronal depolarization in human induced pluripotent stem cell-derived glutamatergic neurons (NGN2) from 6 patients with schizophrenia and 5 control participants.RESULTS:
Multiomic data integration associated global patterns of chromatin accessibility with gene expression and identified enhancer-promoter interactions in glutamatergic neurons. Within 1 hour of potassium chloride-induced depolarization, independent of diagnosis, glutamatergic neurons displayed substantial activity-dependent changes in the expression of genes regulating synaptic function. Depolarization-induced changes in the regulome revealed significant heritability enrichment for schizophrenia and Parkinson's disease, adding to mounting evidence that sequence variation within activation-dependent regulatory elements contributes to the genetic risk for brain-related disorders. Gene coexpression network analysis elucidated interactions among activity-dependent and disease-associated genes and pointed to a key driver (NAV3) that interacted with multiple genes involved in axon guidance.CONCLUSIONS:
Overall, we demonstrated that deciphering the activity-dependent regulome in glutamatergic neurons reveals novel targets for advanced diagnosis and therapy.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Schizophrenia
/
Induced Pluripotent Stem Cells
Type of study:
Etiology_studies
/
Guideline
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Biol Psychiatry
Year:
2024
Document type:
Article