Researchers have revealed the usefulness of a structural protein in potentially diagnosing and treating a variety of genetic disorders linked to DNA disorganisation.
Lamins, encoded by genes LMNA, LMB1 and LMNB2, are fibrous nuclear proteins that form networks of intermediate filaments. They are major components of the nucleoskeleton. They interact with key partners to determine nuclear mechanics, modulate signalling and dynamically organise the genome. The networks interact with heterochromatin in each cell to alter the 3D configurations of individual chromosomes to the nuclear periphery. These silent heterochromatin regions are known as lamina-associated domains (LADs). Current evidence suggests that lamins A and C are the predominant lamins for molecular tethering at the nuclear envelope. While lamin A and lamin C have historically been treated as duplicate proteins as they are from the same gene, there is now growing evidence that suggests that lamins A and C have distinct roles.
In a recent study, published in Genome Biology, researchers sought to better understand the ways in which lamins influence how the cell uses and organises its DNA. The team specifically examined chromosome architecture in mouse cells in which lamin A or lamin C were downregulated.
They found that lamin C, and not lamin A, was essentially responsible for the 3D organisation of LADs and overall chromosome organisation. The team observed notable differences in localisation of the lamins during the cell cycle. Lamin A was associated with the nuclear envelope during telophase. Meanwhile, lamin C was dispersed throughout the nucleus and remained phosphorylated. The researchers believe this implies that modified lamin C helps guide DNA into place during reorganisation. Once the DNA is organised, the lamin then loses its molecular tag and becomes associated with the rest of the lamins at the edge of the nucleus.
These findings raise the possibility of developing new tests that can distinguish between lamins A and C. This could help when screening for some genetic diseases that involve lamin proteins or other proteins at the nuclear envelope. The gene that encodes lamins A and C is associated with inherited diseases that include three forms of muscular dystrophy – familial partial lipodystrophy, progeria and several heart muscle disorders. The team now hope to further identify how lamin proteins and the genome behave when one specific type of lamin is mutated.
Image credit: canva