PhD Project - Molecular genetic analysis of a chromatin-related pathway that is disrupted in several autism spectrum disorders

Vacancy Reference Number

2022-SIDB-BIRD

Closing Date

16 Jan 2022

Address

University of Edinburgh

Background:

Autism is caused by mutations in several hundred different genes, posing a daunting therapeutic challenge. It is possible however that many “autism proteins” converge on a smaller number of key pathways, potentially simplifying approaches to therapy. This project will follow up our preliminary evidence for one such convergent pathway involving proteins that regulate gene expression via modification of chromatin structure.

Rationale & hypothesis:

Our starting point has been Rett syndrome, which is caused by inactivation of the MeCP2 protein. MeCP2 connects DNA methylation with chromatin structure by recruiting the histone deacetylase-containing corepressor complex, NCoR. MeCP2 recruits NCoR by interacting with its TBL(R)1 subunit (Tillotson and Bird, 2019). TBL(R)1 is itself mutated in a range of neurodevelopmental disorders some of which have autistic features (Laskowski et al, 2016). Interestingly, we find that several proteins encoded by genes on the SFARI list (mutated in autism) are recovered by immunoprecipitation of TBL(R)1 as detected by mass spectrometry. These observations suggest that these mutated gene products all impact a common pathway that is critical for brain function. This project aims to work out the molecular details of this potential convergent pathway by defining their molecular interactions and testing biological significance using animal models.

Aims:

• Our unpublished data identifies six proteins that interact, 4 of which are mutated in ASDs. The student will first map interaction surfaces, relating these to the locations of disease mutations for each.
• S/he will then test the hypothesis that these contacts mediate essential functions using cellular and animal models. This will lead to molecular (RNAseq, quantitative proteomics) and behavioural analysis of animal models bearing discrete mutations that specifically disrupt the interactions.
• The hypothesis that convergence leads to competition for contact sites which is disturbed by loss of one component will be explored, as this may have secondary consequences of clinical relevance.

Training outcomes: The candidate will be trained in and will execute all techniques needed to make progress in understanding this pathway and defining its role in brain development and function. Most of these, including molecular cell biology and both cellular and organismal genetic manipulation, are already in use in our laboratory. S/he will present data at weekly lab meetings and attend. and where possible present, at annual Centre for Cell biology and SIDB recesses. Attendance at courses (e.g. in imaging, bioinformatics) is encouraged.