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Epigenetic modifiers of a Mendelian disease and implications for gene therapy.

Supervisors:
Dagan Jenkins and Louise Gregory

Project Description:
Epigenetic modifiers of a Mendelian disease and implications for gene therapy.


Background
It is now widely appreciated that our genes play only a minor role in determining what we look like and what diseases we get. Patients with mutations often exhibit extensive variability in clinical presentation, and even 'identical twins' can have very different appearances. Our bodies are made up of diverse/highly specialised cell types, and yet they all carry the same DNA. One explanation for this variability is epigenetics, a group of mechanisms that lead to the same DNA sequence being presented differently. These differences are inherited as the cells within us divide and, in some cases, across generations, such that our life experiences may affect our grandchildren. The impact of epigenetics in health and disease is only just beginning to be understood.

Known mechanisms of epigenetic variation include DNA methylation and histone modifications that affect the binding of proteins (including transcription and splicing factors) to DNA. The effects of these modifications can be seen in imprinting disorders, rare diseases caused by mutations in enzymes that catalyse epigenetic modifications (EpiEffectors), and examples of transgenerational inheritance. Anecdotal examples of discordant monozygotic twins with rare diseases and variability amongst genetically identical animal models of genetic diseases also suggest that epigenetic modifiers of monogenic disease must exist, but none have been found to date. 

Aims and Objectives

We aim to be the first to identify epigenetic modifiers of human disease by focusing on mutations within splice sites of known disease-causing genes. We know that DNA methylation and histone modifications regulate alternative splicing acting on short co-linear regions of DNA at intron-exon junctions. It is therefore likely that epigenetic modifications within these regions contribute to splicing variability and act as modifiers of monogenic disease. 


Methods 
We work on a group of genes that form the intraflagellar transport (IFT) protein complex responsible for protein transport and signal transduction within cilia1. Previously, we have: 1) Identified phenotypic variation in isogenic models of genetic diseases associated with IFT mutations, and; 2) Correlated this phenotypic variability with variation in RNA splicing and gene expression.

Aim 1) To compile a database of DNA methylation variation and chromatin signatures (histones) at splice sites within IFT genes from publicly available datasets, and predict their effects on pre-mRNA splicing using machine learning/AI.

Aim 2) Use targeted gene-editing and epigenome editing to alter IFT gene mRNA alternative splicing in multipotent/stem cells and evaluate their effects on cilia function.

Aim 3) Generate epigenome-edited mouse models targeting splice sites identified in Aims 1&2 to evaluate the impact of epigenetics on disease variability and treatment. 


Timeline
Year 0-1.5: Training in bioinformatics and machine learning and identification of epigenetic marks affecting splicing in IFT genes.
Year 0.5-2: Designing and cloning reagents for gene-editing and epigenome editing and evaluation in ciliated cells.
Year 1-2.5: Designing epigenome-editing strategies to be used in mice and breeding animals for phenotype characterisation.
Year 2.5-3: Writing up PhD thesis and results for publication.


Publications
https://profiles.ucl.ac.uk/27156-dagan-jenkins/publications
1)doi: 10.7554/eLife.33067. 
2)doi: 10.3390/cells12222662.
3)doi: 10.3390/ijms24054778.
4)https://doi.org/10.1038/s41588-024-01706-w 

Contact Information:
Dagan Jenkins