Understanding the function of LMNA isoforms towards genomic therapies for laminopathies.

Genes are typically made up of multiple exons, forming transcripts that encode proteins. Through multiple mechanisms - splicing and alternative promoters - isoforms can arise. Recent advances in full-length RNA sequencing have uncovered this isoform complexity, identifying novel isoforms. The Biddie and Bickmore groups have recently shown that novel isoforms can have different functions and contribute to genetic diseases (1). Isoforms also have tissue-specific expression, with alternative isoforms of some genes dominating, yet the function and role of these isoforms in disease is not well understood.

This project aims to uncover the function of LMNA isoforms, encoding A-type lamins, which form part of the membrane of the cell nucleus. Genetic variants of LMNA can cause a range of rare disorders called laminopathies, which includes Hutchinson-Gilford progeria, Emery-Dreifuss muscular dystrophy, Familial Partial Lipodystrophy, and dilated cardiomyopathy (2).

Two isoforms, Lamin A/C are well known, but over 20 alternative isoforms have been uncovered by full-length RNA-seq. Their functions are not well understood in the context of genome biology. Understanding isoform activity in cells can inform pathogenic processes of rare variants in laminopathies. Furthermore, isoform engineering can be developed as therapeutic strategies. Recent therapies that use antisense oligonucleotides (ASOs) that induce exon-skipping to form engineered isoforms are being developed for Hutchinson-Gilford progeria (3) but are under-developed for other laminopathies.

1. Computational analysis of full-length RNA-seq from human tissue and cells.
2. Identify functional roles of LMNA isoforms using molecular and cellular methods.
3. Develop and characterise engineered LMNA isoforms towards genomic therapies. 

The Project will develop knowledge and skills in computational, molecular and cellular biology. Computational skills include RNA-seq, genetic variant, and epigenetic analyses (1). Molecular techniques include cloning, genome editing, and RNA and DNA sequencing. Functional assays will include transcriptomics, and imaging-based methods for nuclear structure, and protein dynamics (4).

1. Weykopf et al., 2025; https://doi.org/10.1101/2025.07.24.666385
2. Karoutas and Akhtar, 2021; https://doi.org/10.1038/s41556-020-00630-5
3. Puttaraju et al., 2021; https://doi.org/10.1038/s41591-021-01262-4
4. Gilchrist et al., 2004; https://doi.org/10.1186/1471-2121-5-46