A multiomic atlas for functional genomics in autism

De novo mutations in chromatin modifiers and transcription factors (CMTFs) constitute nearly 70% of the recurrent mutations observed in autism spectrum disorder (ASD) individuals. The majority are loss-of-function mutations.

To date, it has been challenging to identify key molecular and cellular alterations underlying ASD due to a lack of high-throughput methods.

Here I propose to characterize the functional impact of loss of CMTFs at scale — examining how CMTF loss alters epigenetic landscapes, gene expression, neuronal function, cortical layering, and neuronal morphology. To do this, I will develop a suite of multiomic and spatial forward genetic screen technologies.

Using a high- throughput pooled screen in human cortical neurons differentiated from pluripotent stem cells, I will knock-down CMTFs recurrently mutated in ASD and profile the resulting changes in chromatin accessibility and gene expression.

In parallel, I will include natural CMTF variants using ASD patient- derived cells to characterize the impact of genetic background on the penetrance of mutations.

Using brain cortical organoids and spatial transcriptomics, I will examine whether CMTF loss preferentially impacts particular neuron subtypes.

The resulting functional multiomic atlas of cell states after CMTF loss will be a major resource for the community, facilitating the development of new molecular diagnostic biomarkers and the discovery of new therapies for ASD.