Many DNA variants linked with neuropsychiatric disorders (NPD) that do not code for proteins depend on neuronal activation, a study suggests.
The findings, in Science, highlight the power of cell stimulation to reveal context-specific “hidden” genetic effects in conditions such as schizophrenia.
They suggest that genetic regulation is not fully revealed by measuring gene expression alone.
Instead, gene activity—at least in the brain—may depend on context and the physiological state of neurons.
“Liang et al. demonstrate that the genetic processes that underlie neuropsychiatric disease are heavily determined by a dynamic physiological environment rather than by fixed cellular conditions,” said Biao Zheng, PhD, and Panos Roussos, PhD, from Icahn School of Medicine at Mount Sinai in New York, in a Perspective article accompanying the study.
They added: “To understand disease genetics, we might need to study the genome in motion and not at rest.”
Genome-wide association studies have revealed hundreds of genetic loci associated with mental illness, with more than 280 identified for schizophrenia alone.
But many of these DNA regions do not encode proteins and their impact is often subtle and difficult to detect.
To investigate further, Lifan Liang, PhD, from the University of Chicago, and co-workers studied gene expression and chromatin accessibility in single neurons derived from induced pluripotent stem cells collected from a hundred human donors.
The single-cell multi-omics study involved assessing transcriptional and epigenomic profiles before and after neurons were activated through potassium-induced depolarization.
The team found that much of the activity in regulatory DNA regions only became apparent with neuronal stimulation.
Both the number of detectable expression quantitative trait loci (eQTLs)—genetic variants associated with differences in gene expression—and chromatin accessibility QTLs (caQTLs)—DNA variants associated with differences in chromatin accessibility—rose after neuronal stimulation.
Shared and cell type-specific transcription factors worked together, possibly through regulatory cascades, to drive cell type-specific neuronal responses to stimuli.
eQTLs after stimulation had substantially weaker overlap with brain eQTL catalogs derived from postmortem tissue compared with eQTLs before stimulation.
This suggested that many relationships between regulatory DNA activity and gene expression become detectable only during neuronal activation and could be missed by traditional tissue-based studies.
A higher number of caQTLs were associated with neuropsychiatric disease compared with eQTLs, suggesting that disease-associated genetic variants could have detectable effects on regulatory DNA even when downstream changes in gene expression were not obvious.
Supporting this, chromatin accessibility and transcriptional responses to neuronal activation often occurred at different times.
Regulatory regions associated with genes that respond rapidly to neuronal stimulation often remained accessible after transcription subsided. By contrast, some late response genes exhibited accessible chromatin before their expression was induced.
When taken together, these observations implied that chromatin accessibility can be an indication of both prior and future transcriptional potential.
“We identified thousands of cell type–specific and activity-dependent quantitative trait loci for gene expression (eQTLs) and chromatin accessibility (caQTLs), helping prioritize NPD risk variants and genes that manifested functional effects only upon neuronal stimulation,” the researchers asserted.
They added: “Our work provides mechanistic insights on neuron subtype–specific activity-dependent gene regulation, substantially expanding the repertoire of context-specific causal variants and genes for NPD and other brain traits.”
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