Higher-order genome organization in human disease

Abstract

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.

Figure 1.

Higher-order chromatin structure and DNA repair. (A) The condensation status of chromatin affects DNA repair. If a double strand break occurs in more densely packed heterochromatin region, architectural proteins (green) such as HP1, linker histone H1, or HMG proteins, associated with these domains, prevent access of the DNA repair machinery (red) and must be removed, possibly via action of the ATM kinase. Upon removal, the DNA repair machinery can gain more immediate access to the DSBs. (B) In the less densely packed euchromatin regions, the repair machinery has freer access to the DSBs.

Figure 2.

Spatial organization of chromosomes in the formation of cancer translocations. Translocations preferentially occur between proximally positioned chromosomes (red, green), and only rarely between distally located chromosomes (blue). Closely juxtaposed double-strand breaks (yellow stars) occurring at the interface between chromosomes create free chromosome ends, which may recombine to form a chromosome translocation by illegitimate joining.

Figure 3.

Chromatin effects in aging. A complex network of interactions links chromatin structure to aging. Cellular stress may directly induce changes in the epigenetic status of the genome leading to local and global chromatin remodeling, which in turn may make the genome more susceptible to DNA damage. Cellular stress may also cause DNA lesions itself. As part of the cellular response to these lesions, chromatin remodeling events occur and may lead to redistribution of epigenetic modifiers away from their regular binding sites and toward inappropriate targets, thus altering the epigenetic state of the genome. Alterations in global chromatin structure and epigenetic status lead to activation of gene expression programs including specific-aging associated programs such as activation of inflammation and cellular stress responses, but they likely also contribute to random misregulation of genes throughout the genome. These specific and nonspecific misregulation events likely act in a feed-back loop to further destabilize the epigenetic homeostasis of the aging genome.