Molecular mechanisms underpinning chromatin regulation by the MORC ATPases

Transcriptional regulation enables cells with the same genome to differentiate into cells with specialized function.

Epigenetic pathways form an important regulatory layer, for example through DNA methylation and modifications of histones that package DNA into chromatin.

A variety of factors respond to and orchestrate such epigenetic signatures, remodelling chromatin structure and rewiring transcriptional programs. We aim to elucidate the mechanism of chromatin regulation by the microchordia (MORC) ATPases. MORCs maintain genome stability by repressing the transcription of genes and mobile genetic elements.

Their activities are associated with histone and DNA methylation pathways. Gene knockouts cause embryonic lethality in mouse, illustrating key developmental functions.

Patient mutations in MORC ATPase domains cause severe neurodevelopmental disorders.Accurate MORC functions are thus vital to human health. But there are important knowledge gaps. How do MORCs impose transcriptional silencing alongside other epigenetic pathways? Why are particular genetic elements specifically targeted by different family members?

What is the relationship between MORC functions and human neural development?

My team will address these outstanding questions by combining structural biology with functional genomic methods in neural stem cell models.

Through this work we will be ideally placed to address the potential for selective agonism or antagonism in these pathways, as tools and therapies.