Lamin A/C sustains PcG proteins architecture maintaining transcriptional repression at target genes

Beyond its role in providing structure to the nuclear envelope, Lamin A/C is involved in transcriptional regulation. However, its cross talk with epigenetic factors and how this influences physiological processes is still unexplored. Key epigenetic regulators of development and differentiation are the Polycomb group (PcG) of proteins, organized in the nucleus as microscopically visible foci. Here, we show that Lamin A/C is evolutionarily required for a correct PcG proteins nuclear compartmentalization. Confocal microscopy supported by new algorithms for image analysis reveals that Lamin A/C knock-down leads to PcG foci disassembly and PcG protein dispersion. This causes detachment from chromatin and defects in PcG-mediated higher order structures, thereby leading to impaired PcG repressive functions. Using myogenic differentiation as model, we found that reduced levels of Lamin A/C at the onset of differentiation lead to an anticipation of the myogenic program due to an alteration of PcG-mediated transcriptional repression. Taken together, our results indicate that Lamin A/C can modulate transcription through the regulation of PcG epigenetic factors.