Higher-order Genome Organization in Human Disease

Genomes are organized into complex higher-order structures by folding of the DNA into chromatin fibers, chromosome domains, and ultimately chromosomes. The higher-order organization of genomes is functionally important for gene regulation and control of gene expression programs. Defects in how chromatin is globally organized are relevant for physiological and pathological processes. Mutations and transcriptional misregulation of several global genome organizers are linked to human diseases and global alterations in chromatin structure are emerging as key players in maintenance of genome stability, aging, and the formation of cancer translocations.Genomes in their native state are folded into complex higher-order structures. Hierarchical folding of DNA gives rise to chromatin fibers, chromosomes domains, and eventually chromosomes (reviewed in Felsenfeld and Groudine 2003; Belmont 2006; Woodcock 2006). At the lowest level, DNA is wrapped around an octamer of core histone proteins, which are the primary architectural elements of the chromatin fiber, to form a nucleosome. Multiple nucleosomes are linked by stretches of DNA, often occupied by a linker histone, into a beads-on-a string fiber of ∼10 nm in diameter. This primary fiber is then further compacted onto itself to form higher-order fibers of various diameters, although their precise geometry in vivo is unknown (reviewed in Belmont 2006; Woodcock 2006). At the next level of organization, the chromatin fiber folds into subchromosomal domains of ∼1 Mb in size (reviewed in Cremer and Cremer 2001; Cremer et al. 2006). These subchromosomal domains in turn are folded to give rise to an interphase chromosome. In mammalian cells, the degree of fiber compaction from naked DNA to a chromosome is estimated to be on the order of ∼10,000-fold (reviewed in Belmont 2006).During interphase, chromosomes exist as chromosome territories (reviewed in Cremer and Cremer 2001; Meaburn and Misteli 2007; Misteli 2007). A chromosome territory is defined as the nuclear space taken up by the DNA of a given chromosome. The term “territory” refers to the fact that the occupied space is compact, typically roughly ovoid in shape, with a volume of about 2–3 μm in diameter (reviewed in Cremer and Cremer 2001; Meaburn and Misteli 2007; Misteli 2007). The internal structure of chromosome territories is poorly understood but likely consists of a highly interconnected and branched network of channels, which form between looping chromatin fibers (reviewed in Cremer and Cremer 2001; Meaburn and Misteli 2007; Misteli 2007). This relatively open structure allows access of gene regulatory factors into the interior of chromosome territories. Although chromosome territories are discrete structures within the nucleus, neighboring chromosomes can overlap considerably and chromatin loops from one territory can easily invade the body of the neighboring territory (Visser et al. 2000; Branco and Pombo 2006).The higher-order organization of the genome into chromatin fibers and chromosomes is now known to critically contribute to gene regulation (reviewed in Fraser and Bickmore 2007; Lanctot et al. 2007). It is therefore not surprising that defects in higher-order chromatin and chromosome organization cause disease. There is an increasing list of diseases in which changes in histone modifications have been documented, although it is often not clear whether these alterations are a cause or merely a side-effect of the disease process. Furthermore, although many disease-related epigenetic changes have implicitly been assumed to result in changes in higher-order chromatin structure, it is often not clear whether the observed disease phenotypes are because of structural chromatin defects or because of altered gene expression caused by local changes in histone modifications at particular genes. This article focuses primarily on disease mechanisms that involve bona-fide structural defects in chromatin.