Abstract
BackgroundThe dynamic 3D organization of the genome is central to gene regulation and development. The nuclear lamina influences genome organization through the tethering of lamina-associated domains (LADs) to the nuclear periphery. Evidence suggests that lamins A and C are the predominant lamins involved in the peripheral association of LADs, potentially serving different roles.ResultsHere, we examine chromosome architecture in mouse cells in which lamin A or lamin C are downregulated. We find that lamin C, and not lamin A, is required for the 3D organization of LADs and overall chromosome organization. Striking differences in localization are present as cells exit mitosis and persist through early G1 and are linked to differential phosphorylation. Whereas lamin A associates with the nascent nuclear envelope (NE) during telophase, lamin C remains in the interior, surrounding globular LAD aggregates enriched on euchromatic regions. Lamin C association with the NE is delayed until several hours into G1 and correlates temporally and spatially with the post-mitotic NE association of LADs. Post-mitotic LAD association with the NE, and global 3D genome organization, is perturbed only in cells depleted of lamin C, and not lamin A.ConclusionsLamin C regulates LAD dynamics during exit from mitosis and is a key regulator of genome organization in mammalian cells. This reveals an unexpectedly central role for lamin C in genome organization, including inter-chromosomal LAD-LAD segregation and LAD scaffolding at the NE, raising intriguing questions about the individual and overlapping roles of lamin A/C in cellular function and disease.
Highlights
Lamins, encoded by LMNA, LMNB1, and LMNB2, form networks of nuclear intermediate filaments that are major components of the nucleoskeleton
lamina-associated domains (LADs) proximity to the nuclear envelope is maintained by Lamin C To test our hypothesis, we developed short hairpin RNAs that downregulate lamin A or lamin C
The immediate post-mitosis stage, where the nuclei are still rounded up and the cytoskeleton has not yet exerted its influence on nuclear shape may be a relevant point in the cell cycle for lamin A. This finding makes it even more striking that shA-treated cells do not display perturbed lamin organization. These findings collectively demonstrate that lamin C is required for LAD integrity and dynamic LAD recruitment and association with the nuclear envelope (NE) and nuclear lamina after cell division
Summary
Lamins, encoded by LMNA, LMNB1, and LMNB2, form networks of nuclear intermediate filaments that are major components of the nucleoskeleton. Lamin filaments interact with key partners including most nuclear membrane proteins and linked to the cytoplasm through LINC (Linker of Nucleoskeleton and Cytoskeleton) to form nuclear lamina networks that determine nuclear mechanics, modulate signaling, and dynamically organize the genome [1,2,3,4,5,6]. Wong et al Genome Biology (2021) 22:305 configurations of individual chromosomes with respect to the nuclear envelope (NE) These silent heterochromatin regions, identified operationally as lamina-associated domains (LADs), correspond to the “B” compartment identified via HiC and related chromatin mapping strategies [7,8,9]. Evidence suggests that lamins A and C are the predominant lamins involved in the peripheral association of LADs, potentially serving different roles
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