Predicting three-dimensional genome structure from transcriptional activity.

It is often supposed that, except for tandem duplicates, genes are randomly distributed throughout the human genome. However, recent analyses suggest that when all the genes expressed in a given tissue (notably placenta and skeletal muscle) are examined, these genes do not map to random locations but instead resolve to clusters. We have asked three questions: (i) is this clustering true for most tissues, or are these the exceptions; (ii) is any clustering simply the result of the expression of tandem duplicates and (iii) how, if at all, does this relate to the observed clustering of genes with high expression rates? We provide a unified model of gene clustering that explains the previous observations. We examined Serial Analysis of Gene Expression (SAGE) data for 14 tissues and found significant clustering, in each tissue, that persists even after the removal of tandem duplicates. We confirmed clustering by analysis of independent expressed-sequence tag (EST) data. We then tested the possibility that the human genome is organized into subregions, each specializing in genes needed in a given tissue. By comparing genes expressed in different tissues, we show that this is not the case: those genes that seem to be tissue-specific in their expression do not, as a rule, cluster. We report that genes that are expressed in most tissues (housekeeping genes) show strong clustering. In addition, we show that the apparent clustering of genes with high expression rates is a consequence of the clustering of housekeeping genes.

In comparison with many nuclear proteins, the movement of chromatin in nuclei appears to be generally constrained. These restrictions on motion are proposed to reflect the attachment of chromatin to immobile nuclear substructures. To gain insight into the regulation of chromosome dynamics by nuclear architecture, we have followed the movements of different sites in the human genome in living cells. Here, we show that loci at nucleoli or the nuclear periphery are significantly less mobile than other, more nucleoplasmic loci. Disruption of nucleoli increases the mobility of nucleolar-associated loci. This is the first report of distinct nuclear substructures constraining the movements of chromatin. These constraints reflect the physical attachment of chromatin to nuclear compartments or steric impairment caused by local ultrastructure. Our data suggest a role for the nucleolus and nuclear periphery in maintaining the three-dimensional organization of chromatin in the human nucleus.