Chromosome territories and the global regulation of the genome

Abstract

Spatial positioning is a fundamental principle governing nuclear processes. Chromatin is organized as a hierarchy from nucleosomes to Mbp chromatin domains (CD) or topologically associating domains (TADs) to higher level compartments culminating in chromosome territories (CT). Microscopic and sequencing techniques have substantiated chromatin organization as a critical factor regulating gene expression. For example, enhancers loop back to interact with their target genes almost exclusively within TADs, distally located coregulated genes reposition into common transcription factories upon activation, and Mbp CDs exhibit dynamic motion and configurational changes in vivo. A longstanding question in the nucleus field is whether an interactive nuclear matrix provides a direct link between structure and function. The findings of nonrandom radial positioning of CT within the nucleus suggest the possibility of preferential interaction patterns among populations of CT. Sequential labeling up to 10 CT followed by application of computer imaging and geometric graph mining algorithms revealed cell‐type specific interchromosomal networks (ICN) of CT that are altered during the cell cycle, differentiation, and cancer progression. It is proposed that the ICN correlate with the global level of genome regulation. These approaches also demonstrated that the large scale 3‐D topology of CT is specific for each CT. The cell‐type specific proximity of certain chromosomal regions in normal cells may explain the propensity of distinct translocations in cancer subtypes. Understanding how genes are dysregulated upon disruption of the normal “wiring” of the nucleus by translocations, deletions, and amplifications that are hallmarks of cancer, should enable more targeted therapeutic strategies.

The Interchromatin Compartment Participates in the Structural and Functional Organization of the Cell Nucleus

“…The scaffolding protein SAF‐A interacts with chromatin‐associated RNAs and forms a chromatin mesh in a transcription‐dependent manner . Though current evidence favors the perspective that folded chromatin per se forms a structural milieu for nuclear functions, scaffolding structures with a multifaceted biochemical composition and structural organization formed within the ANC may also essentially contribute to shaping the functional nuclear architecture . Some scaffolding structures, including A‐type lamins may start at NPCs and expand into the nuclear interior along the preformed routes of the IC channel system, while others are generated in the nuclear interior .…”

“…During the last two decades, the compartmentalized structure of the cell nucleus and packaging of its genome has become a key issue for the understanding of nuclear functions . Methodological progress has now reached a state where we are witnessing the rise of a new research field, called the 4D nucleome .…”

MYCN overexpression is linked to significant differences in nuclear DNA organization in neuroblastoma

“…It seems that chromosome territories (CT) can mix and form contacts with each other in the absence of DNA poor spaces [41]. CT arrangements are not random, and transcriptionally inactive heterochromatin in the nucleus is preferentially localized along the nuclear periphery [42]. In addition, individual genes that are expressed are typically found more interiorly in the nuclei than those that are not expressed.…”

Introduction to the special issue “3D nuclear architecture of the genome”

“…In this issue, Fritz et al describe current views on chromosome territories and overall genome regulation. The authors discuss cell‐type specific interchromosomal networks (ICNs) of chromosome territories that are altered during the cell cycle, differentiation, and cancer progression.…”

“…While genomes have evolved over millions of years, this structural order is evolutionary conserved as reported for higher primates. 2 In this issue, Fritz et al 3 Understanding the mechanisms that underlie the nuclear structural order and its perturbations is the focus of many studies. We do not have a complete understanding; however, a few key mechanisms have been described.…”