Nuclear envelope regulation and links with disease
The nuclear envelope (NE) lies at the interface between the nucleus and the cytoskeleton. It forms a complex structure that controls cell compartmentalisation and regulates many processes including nucleo-cytoplasmic transport of proteins and RNA, chromatin organisation, DNA replication and DNA repair. For this reason, defects in NE integrity can cause drastic changes in cell homeostasis and are associated with a broad range of diseases including premature ageing disorders such as Hutchinson Gilford Progeria Syndrome (HGPS), as well as with physiological ageing. Our main goal is to identify and characterize new pathways that can modulate NE function.
- Figure 1. 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 wildtype cells (left).
How does NAT10 regulate nuclear envelope function?
One focus of the lab is to study the N-acetyltransferase 10 (NAT10) protein, that I identified as a new regulatory node in NE control. Indeed, targeting NAT10 rescues most cellular phenotypes of HGPS and normal ageing cells. As the mechanisms behind these are still unclear, we are investigating the link between NAT10 and the NE in depth.
- Figure 2. 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.
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.
Identification of new regulatory pathways in premature ageing syndromes
In addition, we are working on identifying new candidates involved in NE control 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. Moreover, the relevance of these new regulatory pathways will be confirmed in vivo in specific mouse models that recapitulate human syndromes associated with NE defects.
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.
Key publications
Larrieu D*, Viré E, Robson S, Breusegem SY, Kouzarides T & Jackson SP*.Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway. Sci. Signaling 10.1126/scisignal.aar5401 (2018). * co-corresponding
Balmus G*, Larrieu D* et al. Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. Nature Comms 10.1038/s41467-018-03770-3 (2018). *equal contribution
Andrew M. Cobb, Delphine Larrieu, Derek T. Warren, Yiwen Liu, Sonal Srivastava, Andrew J.O. Smith, Richard P. Bowater, Stephen P. Jackson & Catherine M. Shanahan*. Prelamin A impairs 53BP1 nuclear entry by mislocalising NUP153 and disrupting the Ran gradient. Aging Cell doi: 10.1111/acel.12506 (2016).
W Chiang*, C le Sage*, D Larrieu, M Demir and Stephen P. Jackson. CRISPR-Cas9D10A nickase-based genotypic and phenotypic screening to enhance genome editing. Sci Rep. 6:24356 (2016).
Larrieu D, Britton S, Demir M, Rodriguez R, Jackson SP. Chemical inhibition of NAT10 corrects defects of laminopathic cells. Science 344(6183):527-32 (2014).
