Farnesyltransferase inhibitor treatment restores chromosome territory positions and active chromosome dynamics in Hutchinson-Gilford progeria syndrome cells

Abstract

BackgroundHutchinson-Gilford progeria syndrome (HGPS) is a premature ageing syndrome that affects children leading to premature death, usually from heart infarction or strokes, making this syndrome similar to normative ageing. HGPS is commonly caused by a mutation in the A-type lamin gene, LMNA (G608G). This leads to the expression of an aberrant truncated lamin A protein, progerin. Progerin cannot be processed as wild-type pre-lamin A and remains farnesylated, leading to its aberrant behavior during interphase and mitosis. Farnesyltransferase inhibitors prevent the accumulation of farnesylated progerin, producing a less toxic protein.ResultsWe have found that in proliferating fibroblasts derived from HGPS patients the nuclear location of interphase chromosomes differs from control proliferating cells and mimics that of control quiescent fibroblasts, with smaller chromosomes toward the nuclear interior and larger chromosomes toward the nuclear periphery. For this study we have treated HGPS fibroblasts with farnesyltransferase inhibitors and analyzed the nuclear location of individual chromosome territories. We have found that after exposure to farnesyltransferase inhibitors mis-localized chromosome territories were restored to a nuclear position akin to chromosomes in proliferating control cells. Furthermore, not only has this treatment afforded chromosomes to be repositioned but has also restored the machinery that controls their rapid movement upon serum removal. This machinery contains nuclear myosin 1β, whose distribution is also restored after farnesyltransferase inhibitor treatment of HGPS cells.ConclusionsThis study not only progresses the understanding of genome behavior in HGPS cells but demonstrates that interphase chromosome movement requires processed lamin A.

The Spatial Organization of the Human Genome

“…DamID has revealed altered genomic interactions for wild-type lamin A compared with those of progerin (49). Treatment with farnesyl transferase inhibitors prevents the accumulation of farnesylated progerin, producing a less toxic mutant lamin A protein, and this also seems to restore the normal radial nuclear positions of chromosomes in the treated fibroblasts (61).…”

Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine production

“…Chromosome territories can reorganize within the nuclear volume upon stimulation of normal dermal fibroblasts into quiescence and senescence. 30,31 This reorganization occurred rapidly, taking only minutes in quiescent stimulated cells, demonstrating the dynamic nature of genome organization and its responsiveness to stimuli. Given this rapid and dynamic response and the importance of TOR in regulating cellular function, significant changes in both genome function and organization could result from TOR repression.…”

Positional changes of a pluripotency marker gene during structural reorganization of fibroblast nuclei in cloned early bovine embryos

“…[5][6][7][8][9][10][11] It has been reported that nuclear positions of genes, chromatin domains and even entire chromosome territories can change during development and cell differentiation. 8,[12][13][14] As an alternative to movements of entire chromosome territories, it was suggested that they may occupy the same nuclear place before and after activation of genes carried by them, whereas giant chromatin loops may form upon transcriptional activation and move such genes far away from their carrier chromosome territory into a nuclear environment favorable for their transcriptional activation and/or the maintenance of transcription. It was hypothesized that giant loops would even allow the formation of co-regulated, spatial clusters of genes located on different chromosome territories.…”