Scientists discover major regulator of schizophrenia that is active during early development

Researchers at Children’s Hospital of Philadelphia (CHOP) have discovered a gene that acts as a master regulator of schizophrenia during the early stages of human brain development.

The team made the discovery using computational models and cell-based experiments to analyze gene transcription networks in large collections of brain tissues. This revealed a disease-relevant core pathway in schizophrenia and a master regulator of the pathway that affects hundreds of downstream genes.

The findings could pave the way for the development of new treatments.

Pinpointing master regulators may help guide us toward priority targets for novel treatments in the future. Because hundreds, or even thousands, of genes may contribute to the risk of schizophrenia, it is crucial to understand which are the most important ones, orchestrating core networks in the disease."
Kai Wang, Study Author

Schizophrenia is surrounded by many unanswered questions

Schizophrenia is a heritable neuropsychiatric disorder that affects around one in 100 adults. Yet, researchers have many unanswered questions about the genetic architecture of this complex disease.
The underlying genomic biology is difficult to understand, but experts have recently proposed an "omnigenic" model, where almost all of the genes within a disease-relevant cell type contribute to a certain neuropsychiatric illness.

However, Wang points out that "not all the genes carry equal weight - the problem is to determine which are more important than others."

Taking a computational biology approach

As reported in the journal Science Advances, Wang and colleagues applied computational systems biology approaches to datasets of samples from patients with schizophrenia and healthy controls.

One dataset, the Common Mind Consortium (CMC), had well-curated brain collections containing adult post-mortem brain tissue. The other dataset was a collection of primary cultured neuronal cells derived from nasal biopsies and this was used to validate the CMC findings.

Using an algorithm to recreate gene transcription networks, the team found that a gene called TCF4 was a major regulator of a genetic pathway involved in schizophrenia.

Previous genomic studies had already identified that the TCF4 is involved in schizophrenia, but little is known about the effects it has.

To investigate the gene’s functional effects, the researchers decreased its expression in neural progenitor cells and glutamatergic neurons derived from induced pluripotent stem cells.

Analysis of three different cell lines showed that once the gene was “knocked down,” the predicted TCF4 regulatory networks were enriched for genes with transcriptomic changes, genes involved in neuronal activity, schizophrenia risk genes and de novo mutations associated with schizophrenia.

Although some of the cellular effects of TCF4 dysregulation have previously been shown in mice, co-author Jubao Duan thinks that disrupting TCF4 gene networks in human stem cell models may generate results that are more translatable to the neurodevelopmental aspects of neuropsychiatric disorders.

Further research could improve precision medicine

The researchers say the findings set the stage for further research, with one direction being to investigate whether master regulators other than TCF4 play a role in schizophrenia.

This could facilitate precision medicine in the field of psychiatric disorders by eventually enabling schizophrenia patients to be classified into subgroups according to how responsive they are likely to be to treatments.

Other approaches could be to pursue single-cell functional genomics studies to assess the cell types that are most influenced by dysregulating gene expression, suggests first author Abolfazi Doostparast Torshizi.

The study is one of the first to successfully combine computational approaches and stem cell-based experimental models to elucidate complex gene networks in psychiatric diseases.

Wang acknowledges that the study has some limitations. The validation was focused on a particular cell type, while other cell types that have been implicated in schizophrenia such as microglia and interneurons may require investigation.

The team writes:

Although our relatively homogeneous two-dimensional neuronal cultures (80 to 95%) have their advantages, they may not reflect the in vivo brain circuit where different cell types interact with each other. Therefore, it would be interesting to interrogate possible cell type–specific effects of TCF4 knockdown in a mixed cell culture or using brain organoids, followed by single-cell RNA-seq (scRNA-seq) analysis.”

Journal reference:

Torshizi, A. D., et al. (2019). Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia. Science Advances. advances.sciencemag.org/content/5/9/eaau4139