Review
Understanding the 3D genome: Emerging impacts on human disease

https://doi.org/10.1016/j.semcdb.2018.07.004Get rights and content

Abstract

Recent burst of new technologies that allow for quantitatively delineating chromatin structure has greatly expanded our understanding of how the genome is organized in the three-dimensional (3D) space of the nucleus. It is now clear that the hierarchical organization of the eukaryotic genome critically impacts nuclear activities such as transcription, replication, as well as cellular and developmental events such as cell cycle, cell fate decision and embryonic development. In this review, we discuss new insights into how the structural features of the 3D genome hierarchy are established and maintained, how this hierarchy undergoes dynamic rearrangement during normal development and how its perturbation will lead to human disease, highlighting the accumulating evidence that links the diverse 3D genome architecture components to a multitude of human diseases and the emerging mechanisms by which 3D genome derangement causes disease phenotypes.

Introduction

The genome, the major hereditary materials of the cell, resides in the nucleus, which serves as the cell’s information processing center and controls the various activities of the cell, such as proliferation, homeostasis and division. Early biochemical and microscopy studies have revealed that the nucleus is not geometrically homogenous but rather highly compartmentalized, with the various nuclear activities organized into discrete, functionally-specialized sub-nuclear structures, called nuclear bodies. For example, the nucleolus, which assembles around the rDNA genes, is the largest nuclear body and the primary site of rRNA biogenesis and assembly of ribosomes [1]. Other types of nuclear bodies include Cajal body, Clastosome, Nuclear speckle, Paraspeckle, Nuclear gems, PML body, Histone locus body, and Polycomb body (reviewed in [2,3]). Moreover, biochemical studies have demonstrated that the two most fundamental nuclear activities, transcription and replication, are also organized in discrete nuclear foci in mammalian nuclei, termed transcription and replication factories, respectively [4,5]. Meanwhile, the nuclear subcompartments near the nucleoli and nuclear envelope (except the nuclear pores) provide a transcriptionally silent microenvironment for heterochromatic regions to reside, which is critical for maintaining the genome integrity.

For the nearly two meters of genomic DNA to fit into the “tiny” nucleus with a diameter at the scale of several micrometers and to function properly, the genome in every human cell, like all the other eukaryotic genomes, is folded into string-like compact structures, chromatin fibers, whose other essential components are proteins and RNAs [6]. Thus, in addition to the primary (i.e., the DNA double helix) and secondary (i.e., the nucleosomes) structures, the genomic DNA in the nuclear space of eukaryotic cells also possesses a higher-order 3D organization (Fig. 1). While it is well established how DNA wraps into nucleosomes, both the underlying mechanisms instructing nucleosomes to fold into chromatin and further to adopt higher-order structures and the molecular details of this process have long remained elusive and debatable. It is only until the past few years, with the significant advance in microscopy-based DNA imaging technologies and the development of high throughput genomic tools for quantitatively measuring chromatin interactions, enormous new insights into chromatin folding and 3D organization have been obtained. For example, recent microscopy studies suggested that chromatin fibers are flexible and disordered chains assembled from both nucleosomes and nucleosome-depleted DNA [7,8], with a diameter ranging from 5 nm to 24 nm in human cells [8]. It is clear that, despite with some intrinsic stochastic properties, the 3D genome organization is nonrandom and of high functional relevance. It also appears that the spatial arrangement of the genome can be adapted to accomplishing cellular functions other than the genome function per se, such as cell migration, mechanotransduction and vision in nocturnal animals (reviewed in [9]).

In this review, we briefly introduce our current understanding of the chromatin folding and the spatial genome organization gained through recent technological developments. We then review emerging evidence linking the disruption of the different components and layers of the 3D genome organization to a range of human diseases, highlighting some of the important questions remaining to be addressed and the potential directions for new technology development in this fast advancing field.

Section snippets

Features of the 3D genome organization in the eukaryotic nucleus

Over the past decade, advances in both microscopic and DNA sequencing-based technologies, especially the development and application of the chromosome conformation capture (3C)-derived high throughput genomic methods for mapping chromatin interactions (Box 1), have yielded remarkable new insights into the chromatin folding principles, the organizational features and the structure-function relationship of the 3D genome [[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]

Implications of the 3D genome hierarchy for human disease

To this end, it appears that chromatin looping, organization into TADs and spatial compartmentalization are three fundamental mechanisms for organizing the genome in 3D and thereby to modulate the DNA-templated nuclear processes, including transcription, splicing, DNA repair and replication. In accordance with their roles in physiological conditions these mechanisms can have potential pathogenic consequences (Fig. 2). For example, during recurrent chromosome translocation events, which

Genome architectural proteins and human diseases

Chromatin architectural proteins act in concert with each other and other genome organizers including transcription factors and ncRNAs to play critical roles in the formation and maintenance of the 3D genome organization, and thus are pivotal in human development, tissue regeneration and disease. Indeed, an increasing number of genes encoding architectural proteins have been linked to a myriad of human diseases, including developmental disorders, neurodegenerative disorders, psychiatric

Conclusions and future prospects

The synthesis of a wide array of technologies ranging from the still rapidly developing DNA imaging technologies to the fast-growing high-throughput genomic tools for mapping chromatin interactions, the CRISPR/CAS genome engineering technology and the computational data analysis and modelling has greatly facilitated our understanding of the physical organization of the genome in the 3D nuclear space. It is becoming clear that the eukaryotic genome is organized as a nested hierarchy that

Competing financial interests

The authors declare no competing interests.

Acknowledgements

This work was supported by the UW Bridge Fund (ZD), ASH Bridge Grant (ZD), and the NIH Common FundU54DK107979.

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