Form follows function: the genomic organization of cellular differentiation

Abstract

The extent to which the nucleus is functionally organized has broad biological implications. Evidence supports the idea that basic nuclear functions, such as transcription, are structurally integrated within the nucleus. Moreover, recent studies indicate that the linear arrangement of genes within eukaryotic genomes is nonrandom. We suggest that determining the relationship between nuclear organization and the linear arrangement of genes will lead to a greater understanding of how transcriptomes, dedicated to a particular cellular function or fate, are coordinately regulated. Current network theories may provide a useful framework for modeling the inherent complexity the functional organization of the nucleus.Louis Sullivan, whose early efforts helped pioneer the development of the skyscraper, is considered one of the most important architects of the last century. However, it is his dictum-"form ever follows function"-for which he is perhaps best known. Just as this imperative has influenced generations of architects, the idea that structure reflects function provides a useful perspective for a biologist's view of the cell. In many ways, the structure and function of cellular and subcellular organelles are inseparable; that is, disruptions in organelle function can lead to perturbations in its structure. Upon inhibition of rRNA transcription, for example, the nucleolus becomes disordered and ultimately disappears (Leung and Lamond 2003). This integration of structure and cellular function allows for conservation of resources and facilitates regulation at multiple levels.Although a completely sequenced genome may represent a genetic blueprint, molecular biologists currently lack a key with which to fully grasp how this sequence is related to the development and subsequent maintenance of a given organism. Following Sullivan's example, a comprehensive understanding of genomic sequence may require considering its arrangement in the nucleus; the form DNA takes in the nucleus reveals not only its higher-order structure, but it may impart information regarding its function. The current paradigm of gene regulation includes the binding of site-specific transcription factors, the recruitment of cofactors and general transcription factors, and the incorporation of multiple modifications to both the DNA and the histones that organize it (Felsenfeld and Groudine 2003). This description of transcription belies its enormous complexity, fueled by an ever-increasing catalog of proteins dedicated in one way or another to its regulation. Additionally, evidence supporting the role of nuclear localization in transcriptional regulation indicates that it is insufficient to know the components of transcription . Rather, a thorough understanding of the process requires knowing its functional organization within the nucleus. In this sense, transcription should not be viewed simply as a process that turns on a specific gene, but as a process that governs within the genome an entire network of genes (a transcriptome) that gives rise to a p...

Radial chromatin positioning is shaped by local gene density, not by gene expression

“…Such patterns have been found evolutionarily conserved over several hundred millions of years (Alexandrova et al 2003;Federico et al 2006;Habermann et al 2001;Neusser et al 2007;Postberg et al 2005;Tanabe et al 2002) and illustrate that the radial arrangement of chromatin in the interphase nucleus represents a basic principle of nuclear architecture (for review, see Foster and Bridger 2005;Kosak and Groudine 2004;Misteli 2004;Pederson 2004;Zink 2006).…”

“…There is still a lack of comprehensive data on how the distinct segments of metaphase chromosomes are folded into variably shaped chromosome territories (CTs). Furthermore, the extent to which chromatin folding and gene positioning within the nuclear and/or CT space are causally related to a given pattern of gene expression has remained a matter of controversial discussions (Bartova and Kozubek 2006;Kosak and Groudine 2004;Lanctot et al 2007;Parada et al 2004). …”

Three-dimensional positioning of genes in mouse cell nuclei

“…Apart from molecular factors binding directly to DNA and changes in the local chromatin environment, the nuclear organization of chromatin has come into focus as a potential level of genome regulation (for reviews see Kosak and Groudine 2004;Foster and Bridger 2005;Cremer et al 2006;Fraser and Bickmore 2007;Lanctôt et al 2007;Meaburn and Misteli 2007;Misteli 2007). To understand this level of genome organization, it is essential to know the three-dimensional distribution of the genome.…”

Chromatin accessibility and epigenetic modifications differ between frequently and infrequently rearranging VH genes

“…In thymocytes, however, the inactive IgH locus is mainly localized at the nuclear periphery through an interaction with the nuclear lamina or its associated proteins, but not with centromeric heterochromatin (Kosak et al, 2002). Increasing evidence supports the role of the nuclear periphery as a repressive compartment for transcriptional silencing in higher eukaryotes (Kosak and Groudine, 2004). Therefore, although our chromatin accessibility study indicates that V H S107 genes are accessible in their coding and RSS region in thymocytes, the pericentric localization of the IgH locus may be sufficient to inhibit any chance of V H -to-DJ H recombination in those cells.…”