Individuals with autism spectrum disorders (ASDs) exhibit phenotypic diversity that reflects the complex genetic architecture of this group of conditions, which is influenced by hundreds of rare variants of large effect as well as common variants of small effect. A recent large-scale exome-sequencing study has pointed to 102 ASD-associated risk genes1. More than half of these genes encode for regulatory proteins, including transcription factors, chromatin remodelers and, more broadly, chromatin-associated proteins. However, the regulatory programs and gene networks implicated in ASDs remain largely uncharacterized. This limits our progress towards biological understanding and therapeutic intervention.
Here, Kasper Lage and colleagues will pilot an effort to define the regulatory landscape of ASD susceptibility genes in human neurons by identifying the regulatory networks of several transcription factors, including TCF4, CHD8, DYRK1A and GIGYF1, which have all been selected from the aforementioned exome-sequencing study as risk factors for ASD. The team have generated protein-protein interaction data for these transcription factors in human induced pluripotent stem cell (iPSC)-derived glutamatergic excitatory neurons (unpublished data, funded in part by a previous SFARI grant)—the cell model that they also propose to use here.
Specifically, Lage’s team will perform genome-wide chromatin-binding profiling experiments using a new method based on the ‘Cleavage Under Targets & Release Using Nuclease’ (CUT&RUN) protocol2. This will allow the researchers to detect interactions between proteins and DNA in a way that overcomes some of the problems encountered with traditional chromatin immunoprecipitation protocols.
They then plan to use integrative computational methods to associate the resulting regulatory networks with genome-wide association studies (GWAS) and exome sequencing data from ASD cohorts (including the Simons Simplex Collection and SPARK) to identify the subnetworks and sets of target genes most enriched in ASDs. In addition, they aim to produce a consolidated network of the target genes that are both shared and unique to each transcription modulator. This will lead to an overall view of regulatory pathways implicated in these disorders. The data, protocols, reagents and algorithms developed for this project will be shared with the scientific community.
Overall, this pilot study will identify new pathobiological mechanisms associated with ASDs, as well as contribute experimental and computational technologies that will allow researchers to gain insights into the gene regulatory networks implicated in ASDs in human neurons. The findings will contribute to laying the foundation for a better understanding of these neurodevelopmental conditions and guide therapeutic endeavors.
- Spatiotemporal and cell-type convergence to reveal autism neurobiology
- Mapping ASD regulatory networks at cellular resolution in neurodevelopment
- Building phenotypic maps based on neuronal activity and transcriptional profiles in human cell models of syndromic forms of ASD
- Leveraging a high-throughput CRISPR screen to assess convergent neurogenesis phenotypes across autism risk genes
- Brain protein networks perturbed by autism risk genes
- Molecular signatures of autism genes and 16p11.2 deletion