About The Lab
A key goal of the research in the Larrieu's lab is to better understand the roles and regulation of the nuclear envelope (NE) and how defects in these can cause human pathologies. As a postdoctoral fellow in the lab of Steve Jackson in Cambridge, Delphine developed a strong interest in understanding nuclear envelope function in cell integrity and homeostasis, and its links with disease. More specifically, she focused on the nuclear architecture proteins Lamin A and C, whose mutations are associated with genetic diseases including the devastating premature ageing syndrome Hutchinson-Gilford Progeria Syndrome (HGPS). Through an original approach combining phenotypic-based screens and click-chemistry, together with cellular and biochemical assays, as well as in vivo mouse models, she identified and characterised a new small molecule that she called Remodelin. This showed unprecedented improvement of HGPS phenotypes in cells and in vivo models, by targeting the N-acetyltransferase NAT10 and its effects on microtubule organisation.
High resolution microscopy images showing the nuclear envelope in a normal cell (left) compared to a progeria cell (right).
How does NAT10 regulate nuclear envelope function?
One of the research focus in the lab in on NAT10. Through combining biochemical, proteomics, advanced microscopy techniques and biophysical approaches, we are exploring further how NAT10 functions in normal and ageing cells and how its inhibition improves chromatin structure and nuclear shape and reduces DNA damage.
We identified Remodelin by screening for new compounds that can improve phenotypes of cells from Hutchinson Gilford Progeria Syndrome. We showed that Remodelin acts by targeting a protein called NAT10. We are currently investigating the molecular mechanisms behind this rescue.
Identification of new regulatory pathways in premature ageing syndromes
Another important research direction in the lab focuses on identifying new “synthetic rescue” pathways in premature ageing by carrying out complementary high throughput crispr-cas9 genetic and chemical screens. The function of isolated hits will be characterized further in normal and in patient-derived cells, by assessing cellular fitness-related parameters.
Our work will thus improve our understanding of NE regulation and identify new druggable regulators of the NE that might thus yield novel therapies for NE-associated diseases.
High resolution immunofluorescence images showing nuclear envelope staining (green) and nucleolar staining (red and blue). Progeria cells (right) display characteristic nuclear envelope deformation compared to normal cells (left).
Hutchinson Gilford Progeria Syndrome
Hutchinson Gilford Progeria Syndrome (HGPS) is a rare syndrome that triggers very rapid ageing in kids and for which there is currently no cure. HGPS is caused by a single mutation in a nuclear envelope gene called LMNA. As a consequence of this mutation, the nuclear envelope structure is affected, leading to misshapen nuclei (as shown on the picture above), as well as to drastic changes in the organisation of the DNA and in the regulation of gene expression, triggering DNA damage accumulation. The kids experience growth failure as well as most symptoms that also arise in normal ageing, such as hair loss, fat loss, joint stiffness and heart defects.
Current lab members
Sophia Breusegem, PhD
Postdoctoral Research Associate
Funded by the Wellcome Trust
Background and research interests
I am a postdoctoral research associate in Delphine’s lab. While I obtained my PhD in Biophysics and Computational Biology, I now consider myself a cell biologist, fascinated by the intricate molecular processes that happen in our cells. I have particular expertise in quantitative, high-content and high-resolution fluorescent imaging. In Delphine’s lab I am interested in trying to understand the cell biology of the nuclear envelope in both health and disease. My previous research was in the field of membrane trafficking (retromer and renal ion transporters).
Funded by the BBSRC
Background and research interests
Having finished a Bachelor's degree in Natural Sciences from the University of Cambridge, specialising in Biochemistry, Jonathan proceeded to carry out a Master's degree at the same institution. Throughout this time he maintained an interest in molecular and cell biology, with a specific regard to how pathways were altered in relation to diseases. Before beginning his PhD with Delphine Larrieu at the Cambridge Institute for Medical Research, he had conducted shorter projects on a diverse range of subjects including X chromosome inactivation and the repair of DNA damage. He is currently interested in the mechanistic basis behind the phenotypic rescue of Hutchinson-Gilford Progeria cells and mice upon NAT10 inhibition.
Cambridge Translational Biomedical Research MPhiL