Investigating the function of an autism-associated chromatin remodelling factor in brain development

Autism-spectrum disorders (ASDs) affect more than 1/110 individuals in the population, yet the aetiology of ASDs is not understood. Recently, genome-wide approaches have identified several, independent loss-of-functions mutations in the CHD8 gene, which encodes a chromatin remodelling enzyme, in patients with autism (1-3). This identification of CHD8 as a highly significant risk gene for autism provides us with a unique opportunity to investigate the developmental mechanisms that underlie this condition.

In standard laboratory cell lines, CHD8 has been shown to interact with nuclear mediators of WNT signalling (-catenin) and apoptosis (p53) and antagonise their transcriptional activity by recruiting histone 1 (H1) to target promotors. We hypothesise that upregulated and expanded WNT--catenin signalling during different stages of neural development underlies brain defects responsible for ASDs. However, the regulatory elements to which CHD8 is recruited and the genes and pathways regulated by CHD8 during neural development are not known. Chd8 gene deletion in mouse embryos results in early embryonic lethality, and as a result, the function of Chd8 during later stages of development when the brain develops, is not known.

We have generated a new conditional mouse line that will allow us to bypass the early embryonic lethality and investigate Chd8 functions specifically in neural progenitors of the developing brain. In addition, we have developed new antiserum that will allow us to identify the regulatory elements associated with CHD8 in neural progenitors using Chromatin Immunoprecipitation (ChIP) assays, followed by next generation sequencing (ChIP-seq).

The aim of this project will be to identify the functions of CHD8 in brain development and to identify the molecular genetic pathways deregulated by the loss of Chd8 in neuronal progenitors.

To achieve this goal, the student will:
1) delete Chd8 specifically from the embryonic neocortex using an Emx1Cre line
2) analyse the effects of Chd8 deletion on regionalisation of the neocortex, neuronal migration, maturation and synaptogenesis
3) use genome-wide next-generation sequencing approaches to identify the genes and signalling pathways affected by Chd8 loss and the gene promotors and regulatory elements to which CHD8 is recruited in neuronal progenitors.
4) Perform behavioural analysis on Chd8-deficient mice.

This project will provide important insights into the developmental mechanisms that underlie autism in the context of a novel, highly significant genetic defect. The student will join a multi-disciplinary group at King’s (Craniofacial Development and Stem Cell Biology, MRC Centre for Developmental Neurobiology and Institute of Psychiatry) with strong international collaborations in epigenetics of autism (Reinberg, NYU). During the course of the project, the student will gain experience in state-of-the-art mouse genetics, ChIP-seq and RNA-seq techniques, the analysis of WNT signalling in neural development and rodent behaviour and have the opportunity to interact with leaders in the areas of psychiatric epigenetics and development.

NOTE: This project is an example of the kinds of projects available. Similar and related projects using for example zebrafish models are also available - please enquire.