Understanding laminopathies: Diseases of the cell nucleus

Our project uses innovative genome engineering techniques to study laminopathies, diseases of the cell nucleus, to better understand and find treatments for these conditions.

Laminopathies are diseases that affect various tissues in the body. They occur because of mutations in a protein called lamin A, which is found at the edge of the cell nucleus.

Lamin A, along with lamin B, forms a supportive mesh inside the nuclear envelope. Mutations in the lamin A gene can cause diseases such as premature ageing, muscular dystrophies, dilated cardiomyopathies and lipodystrophies

In the past 15 years, we've learned that nuclear lamina proteins are essential for cell health and function.

These proteins protect our DNA from damage, help it replicate correctly, and ensure genes are turned on or off at the right times during the day and throughout our lives.

Mutations in lamin A not only cause many diseases but also contribute to ageing by producing harmful versions of the protein that disrupt cell function.

Understanding how this protein works and finding ways to keep it healthy is essential for improving overall cell health and preventing related diseases.

At Brunel University London, we use advanced methods and technologies to study how specific mutations affect cells.

We introduce these mutations into lab-grown cells, including stem cells, using genome engineering.

Our team has the expertise and equipment to explore how these mutations impact the organisation and behaviour of the genome.

We aim to find new treatments or repurpose existing ones for diseases such as Dilated Cardiomyopathy (DCM) and Hutchinson-Gilford Progeria Syndrome (HGPS).

Using genome engineering in laminopathy research

Using patient cells for research can be challenging due to difficulties in obtaining them and different tissue types and variations between individuals. A trio of family cell lines can be useful with patients and both parents. This is also not always easy to obtain.

Cells from patients, especially those with premature ageing, may not grow well in the lab, limiting the experiments we can perform.

To overcome these challenges, we are creating new cell models with specific laminopathy mutations using genome engineering.

This allows us to generate large amounts of data from many cells with the same genetic background. We use techniques such as CRISPR and RNA interference to introduce DCM and HGPS mutations into normal and stem cells.

We then study how these mutations affect the structure and function of the nucleus and genome using various advanced techniques.

Our goal is to use these cell models to discover new drugs and treatments and explore the potential of genome engineering in these cells as they develop into different cell types.

Our techniques

To develop new cellular model systems for studying laminopathies, we are employing CRISPR and RNA interference to generate the DCM and HGPS mutations in normal cells and in induced pluripotent stem cells (iPSC). Following this, we'll investigate the impact of these mutations on nuclear and genome structure, organisation and function.

We'll use techniques such as DNA adenine methyltransferase identification to identify lamina-associated domains (LADs), DNA and RNA sequencing, chromatin immunoprecipitation (ChIP), fluorescence in situ hybridisation (FISH), bioimaging with super-resolution microscopy and image and data analysis.

The idea is that these cells will be an important tool for finding new and repurposed drugs and treatments. It's unclear whether genome engineering is possible in these cells and what the impact is as they differentiate into specific relevant cell types.