Modulation of nuclear lamin-chromatin interactions by external cues

Abstract

The three-dimensional (3D) organization of chromatin in the mammalian cell nucleus plays an important role in the regulation of gene expression. In her Ph.D. thesis, Anna Frida Forsberg has investigated the impact of distinct stimuli on how structural proteins of the nucleus, A- and B-type lamins, participate in 3D genome organization. Identification of genome domains interacting with A- and B-type lamins by chromatin immunoprecipitation shows that in liver cancer cells, A- and B-type lamins associate with both overlapping and distinct domains. Treatment with Cyclosporin A, an immunosuppressive drug which affects transcription factor binding to chromatin, has little effect on chromatin interactions with B-type lamins; in contrast, interactions with A-type lamins are for the most part lost or instead switch to B-type lamins. Fluorescence in situ hybridization shows that genomic domains that gain lamin B are repositioned towards the nuclear periphery, yet without major changes in gene expression. Forsberg also investigated how 24-h (circadian) rhythms affect lamin-chromatin interactions in mouse liver. Strikingly, most of these interactions are stable throughout the circadian cycle. Nevertheless, several genome regions display rhythmic interactions with nuclear lamins, with defined periods of 12, 18, 24 or 30 h. Such periodic lamin-chromatin interactions are however surprisingly independent of changes in the expression of circadian genes. The findings altogether show that A- and B-type nuclear lamins dynamically associate with common but also distinct parts of the genome to modulate 3D genome architecture in response to specific cues.