The authors took a genome-wide approach to identify the genes concerned. They found that, 5 days after production of progerin was increased, the expression of almost 200 genes was dramatically affected, a number that rose to more than 1,000 by day 10. To interpret this striking effect, they searched for cellular pathways in which several progerin-responsive misregulated genes function; this led them to the Notch signalling cascade, which regulates stem-cell differentiation and cell fate. In cells derived from patients with HGPS, the components of Notch signalling were also abnormally active.
The main tissues affected in HGPS are those of mesenchymal origin, including bone, fat and cartilage. The authors looked at the effect of progerin overexpression — and so Notch activation — on normal human mesenchymal stem cells and found that it led to sporadic but spontaneous differentiation of these cells. Next, they triggered differentiation of mesenchymal stem cells into specific lineages in the presence of progerin: increased stem-cell differentiation into the bone lineage was the result. By contrast, progerin seemed to hinder stem cells' transformation into fat cells. These results are consistent with the fact that patients with HGPS have a high turnover of bone but suffer from a loss of subcutaneous fat.
This is a preview of subscription content, access via your institution
