- Awarded: 2018
- Award Type: Research
- Award #: 572080
The prefrontal cortex (PFC) is critical for social communication and the integration of the cognitive, affective and motivational domains. Various anatomical and functional changes have been described in the PFC of individuals with autism spectrum disorder (ASD), specifically in the orbitofrontal and medial PFC. Previous work in Nenad Sestan’s laboratory, in conjunction with the laboratory of Matthew State, has identified a convergence of autism risk alleles in human PFC at the midfetal stage, a crucial developmental period during which specification of subdivisions of the PFC occurs1. Thus, studying the regulatory and transcriptional mechanisms of human PFC development is likely integral to understanding the pathophysiology of ASD and identifying novel treatments.
To study the process of specification in the midfetal human PFC, Sestan and his team compared expression profiles from four subdivisions of the midfetal PFC; their preliminary analyses identified a gene network enriched in the orbitofrontal cortex that included multiple ASD risk alleles. The current proposal aims to identify conserved and human-specific gene regulatory elements in this novel gene regulatory network, to assess whether they are required for PFC development and to determine whether they are compromised in ASD.
To achieve this, Sestan’s team proposes a comprehensive survey of the transcriptome using tissue and single nuclei genomic techniques in different areas of the PFC from both human and nonhuman mammals during midfetal development. In addition, the team of researchers will utilize ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) combined with other genomic data sets to identify putative regulatory elements active in the four subdivisions of midfetal PFC in the multiple species. Finally, they will use CRISPR-based targeted deletion/insertion mouse lines to assess the functional significance of conserved aspects and non-conserved elements of this pathway. Upon completion of this project, Sestan and his team hope to generate a resource to identify other gene regulatory pathways and candidate genes potentially involved in the etiology of ASD.
- A functional genomic analysis of the cerebral cortex
- Functionally characterizing noncoding regulatory mutations in the Simons Simplex Collection
- Assessing the functional effects of enhancer mutations identified in the Simons Simplex Collection via mouse models
- Investigating cell type-specific molecular pathology in autism