The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells

TLDR

Genome function depends on integrating linear genetic maps with spatial chromosome positioning, and nuclear membrane proteins are thought to anchor chromatin at the periphery—a process that may underlie disease and has been shown to give distinct nuclear addresses to some chromosomes. The study aimed to determine whether chromosomes 18 and 19 serve as a paradigm for chromatin organization in the human nucleus. The authors analyzed the nuclear organization of every human chromosome in diploid lymphoblasts and primary fibroblasts. Gene‑rich chromosomes are centrally located while gene‑poor chromosomes are peripheral, chromosome size does not predict position, and emerin deficiency does not alter this arrangement, indicating emerin is not required for chromatin localization and the muscular dystrophy phenotype is not due to gross nuclear organization changes.

Abstract

To fully understand genome function, the linear genome map must be integrated with a spatial map of chromosomes in the nucleus. Distinct nuclear addresses for a few human chromosomes have been described. Previously we have demonstrated that the gene-rich human chromosome 19 is located in a more central position in the nucleus than the similarly sized, but gene-poor, chromosome 18. To determine whether these two chromosomes are a paradigm for the organization of chromatin in the human nucleus, we have now analysed the nuclear organization of every human chromosome in diploid lymphoblasts and primary fibroblasts. We find that the most gene-rich chromosomes concentrate at the centre of the nucleus, whereas the more gene-poor chromosomes are located towards the nuclear periphery. In contrast, we find no significant relationship between chromosome size and position within the nucleus. Proteins of the nuclear membrane or lamina are candidates for molecules that might anchor regions of the genome at the nuclear periphery and it has been suggested that disruption of this organization may play a role in some disease pathologies. We show that the intranuclear organization of chromosomes is not altered in cells that lack the integral nuclear membrane protein emerin, from an individual with X-linked Emery--Dreifuss muscular dystrophy. This suggests that emerin is not necessary for localizing chromosomes at the nuclear periphery and that the muscular dystrophy phenotype in such individuals is not due to grossly altered nuclear organization of chromatin.