Molecular mechanisms linking nuclear lamina and chromatin organisation

The nuclear lamina (NL), partly composed of lamin-A/C proteins, plays key roles in maintaining nuclear structural integrity and chromatin organisation with profound effects on genome transductions and cellular functions. Deregulation of lamin-A/C results in chromatin disorganisation and is associated with premature and physiological cellular ageing. However, mechanistic understanding of the reciprocal functional relationship between NL and chromatin organisation remain challenging.

After discovering that a key role for the lysine acetyltransferase KAT5 is sensing and transducing chromatin perturbation signals, we hypothesised that this pathway may mechanistically couple NL and chromatin organisation. Accordingly, we found that KAT5 is activated in lamin-A/C defective cells as well as in cells treated with lysine deacetylase (KDAC) inhibitors. We will use novel reagents and develop new experimental tools to determine: whether KAT5 mediates further chromatin disorganisation in lamin-A/C-defective cells and whether chromatin perturbations influence nuclear lamina in a manner that involves KAT5.

Achieving these goals will provide the basis for further investigations into the reciprocal crosstalk between nuclear lamina and chromatin organisation with the long-term vision of understanding the fundamental principals underlying genome organisation/regulation and their relevance to human ageing.