The architecture of functional neighborhoods within the mammalian cell nucleus

Abstract

There is growing realization that the spatio-temporal positioning of functional sites and factors within the cell nucleus are critical determinants of genomic function and regulation within the interphase cell nucleus. Previous studies from our group identified higher order functional zones of replication and transcriptional activity in chromatin domains replicated in early S phase where actively transcribed genes are enriched. It was proposed that these higher order zones represent the modular basis for the coordinate regulation of genomic replication and transcription in the cell. In this article we review our recent findings concerning the spatio-temporal dynamics of early S phase replicated chromatin domains, sites of gene transcription and associated protein factors. Our findings led us to propose that an important step in activation for transcription in the cell nucleus is the unfolding of regions within the discrete chromatin domains so that transcriptionally active chromatin can interact with the machinery for transcription such as RNA polymerase II and the multitude of additional factors involved in transcription and its regulation. Regulation of transcription from this global perspective likely involves temporal programming for the coordinate and differential unfolding of chromatin regions in accordance with the transcriptional programming of the cell. For example, active genes from different chromatin domains could undergo transcription at common sites or transcription factories. In addition, genes regions from within the same chromatin domains could be active at different transcription factories. All this is likely made possible by the spatial arrangement of the protein factors involved in the replicational and transcriptional processes which form combinatorial arrays that define the functional landscape of the cell nucleus. Our results demonstrate a degree of precision for the higher order spatial arrangement of these combinatorial arrays of functional components. It is thus conceivable that alterations in the spatial organization of these arrays could lead to dysfunction or altered regulation of replicational or transcriptional processes at the global level. Studies of the nuclear matrix associated proteins matrin 3 and SAF-A further suggest that anchoring to the nuclear matrix architecture may be a critical determining factor in the combinatorial properties and for the higher order arrangement of these genomic functional complexes into 3-D network-like arrays.