Locking the genome: nuclear organization and cell fate

Abstract

The differentiation of pluripotent or totipotent cells into various differentiated cell types is accompanied by a restriction of gene expression patterns, alteration in histone and DNA methylation, and changes in the gross nuclear organization of eu- and heterochromatic domains. Several recent studies have coupled genome-wide mapping of histone modifications with changes in gene expression. Other studies have examined changes in the subnuclear positioning of tissue-specific genes upon transcriptional induction or repression. Here we summarize intriguing correlations of the three phenomena, which suggest that in some cases causal relationships may exist.

Figure 1

Major nuclear reorganization events over the course of cell fate acquisition. During differentiation, the genome gets globally compacted (upper left third), with clusters of compact chromatin being located close to the lamina (red meshwork) at the nuclear periphery or the nucleolus (light grey), leaving gaps or channels between large chromatin masses. Based on C. elegans studies, gene copy number is seen to influence nuclear localization (upper right third). In embryonic cells, heterochromatic high copy number repeats are located at the nuclear rim while low-copy repeats do not show preferential localization. During differentiation, activation of promoters is able to overcome the anchoring at the nuclear periphery. Preferential localization at the nuclear lamina is observed for silent tissue-specific promoters, while active tissue-specific promoters are more likely to be internal. Gene and chromatin associated dynamics decrease progressively as cells differentiate (lower third). This is correlated to the disappearance of some remodelers and the increase of anchored compact chromatin domains.