Regulating the mammalian genome: The role of nuclear architecture

A new view of the mammalian cell nucleus is emerging based on genomic function. Labeling sites of replication and transcription and visualizing these sites with three-dimensional fluorescence microscopy and computer imaging have led to important advances in our understanding of the relationships of nuclear architecture and genomic function. We determined that each site of replication in early S phase contains an average of about 1 mbp of DNA and is likely organized into a series of chromatin loops termed MLC (multi-loop chromatin) domains. Further studies reveal that the MLC domains are a fundamental property of higher-order chromatin organization in the cell nucleus. Simultaneous labeling of DNA replication and transcription sites coupled with computer image analysis demonstrated that the replication and transcription sites are separately clustered into "zones" of replication or transcription. These higher-order zones form three-dimensional networks in the cell nucleus with the replication network completely separate in 3-D space from the transcription network. A summary model is shown in Fig. 6 which illustrates the functional levels of higher-order chromatin organization from individual chromatin loop domains to MLC domains to the nuclear zones composed of multiple MLC domains. All of these levels of chromatin organization as well as entire chromosome territories are associated with the nuclear matrix. This supports a fundamental role for nuclear architecture in genomic function as well as in the regulation and coordination of the replication and transcription programming of the cell.