Loss of lamin A function increases chromatin dynamics in the nuclear interior.

I Bronshtein,S Mai,Y Garini,E Kepten,Y Shav-Tal,S Gonzalo,Abena B Redwood,I Kanter,R Foisner,S Berezin,M Lindner

doi:10.1038/ncomms9044

Abstract

Chromatin is organized in a highly ordered yet dynamic manner in the cell nucleus, but the principles governing this organization remain unclear. Similarly, it is unknown whether, and how, various proteins regulate chromatin motion and as a result influence nuclear organization. Here by studying the dynamics of different genomic regions in the nucleus of live cells, we show that the genome has highly constrained dynamics. Interestingly, depletion of lamin A strikingly alters genome dynamics, inducing a dramatic transition from slow anomalous diffusion to fast and normal diffusion. In contrast, depletion of LAP2α, a protein that interacts with lamin A and chromatin, has no such effect on genome dynamics. We speculate that chromosomal inter-chain interactions formed by lamin A throughout the nucleus contribute to chromatin dynamics, and suggest that the molecular regulation of chromatin diffusion by lamin A in the nuclear interior is critical for the maintenance of genome organization.

Highlights

Chromatin is organized in a highly ordered yet dynamic manner in the cell nucleus, but the principles governing this organization remain unclear
To gain further insight into genome organization within the nucleus, we focused on the effect of lamin A on the dynamic properties of different genomic regions in live cells
To explore the organizational mechanisms of the genome in the nucleus, we studied the dynamics of different genomic regions in the nucleus of live cells, repeating the measurement in different cell lines and different genomic loci

Summary

Results

Live cell imaging of telomeres in the nucleus. To address these questions, we analysed the movement of fluorescently tagged genomic regions in living cells. Lamin A depletion led to much faster genome dynamics (Supplementary Movies 2 and 3), as well as larger nuclear areas scanned, as demonstrated by plotting telomere and centromere movement areas in different cells (Fig. 3a–c and Supplementary Table 1) These results reveal an unrecognized role of lamin A in chromatin dynamics. To test if the anomalous subdiffusion results from an active process or through genome packaging, we measured ATP-depleted cells and cells under osmotic stress, (Supplementary Fig. 6, 201 and 214 telomeres, respectively). If that is the dominant mechanism, the dynamic properties of genomic sites should mainly depend on their distance from the lamina To test this concept, we measured the diffusion of peripheral and interior telomeres (Fig. 3d). Can explain the short time-range anomalous diffusion that is measured with or without lamin A33

Discussion

Methods

Find the time average MSD of the average particle with