Replication and transcription: Shaping the landscape of the genome

Abstract

DNA replication in mammalian nuclei is carried out in specialized structures that are known as replication factories. Throughout S phase, these factories assemble dynamically, and replicons that are located in their vicinity are recruited to the replication sub-compartment. GC-rich, gene-dense regions tend to replicate early in S phase, whereas AT-rich regions that are usually gene-poor replicate late. In many cases, expressed genes replicate early in S phase and silent genes replicate late, but there are many exceptions to this rule. Early replication timing is probably determined by epigenetic information and chromatin structure rather than by individual gene expression per se. Gene expression does not seem to be a direct consequence of early replication. Transcription is highly compartmentalized in mammalian nuclei. Nascent transcription by RNA polymerase II occurs in foci that are known as transcription factories. Cells contain very few transcription factories compared with the number of active genes. Most 'active' genes are not continuously transcribed, but undergo transcription cycles. Modulation of expression might occur by changing the frequency or duration of the 'on' state versus the 'off' state. On activation, genes migrate to pre-assembled transcription factories that are shared with other actively transcribed genes. In higher eukaryotes approximately 15% of the genome is transcribed. Most transcribed genomic regions are intergenic sequences. The finding that most of the genome is transcribed indicates that transcription factories are principal focal points for the nuclear organization of the genome. The clustering of genes around functional sites in the nucleus might impose selective pressures on the organization of genes and regulatory elements at the primary sequence level, thereby contributing to the observed clustering of highly expressed genes in the genome.