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Review
. 2019 Jun 19:10:602.
doi: 10.3389/fgene.2019.00602. eCollection 2019.

Finding Friends in the Crowd: Three-Dimensional Cliques of Topological Genomic Domains

Philippe Collas  1   2 , Tharvesh M Liyakat Ali  1 , Annaël Brunet  1 , Thomas Germier  1
Affiliations
Review

Finding Friends in the Crowd: Three-Dimensional Cliques of Topological Genomic Domains

Philippe Collas et al. Front Genet. .

Abstract

The mammalian genome is intricately folded in a three-dimensional topology believed to be important for the orchestration of gene expression regulating development, differentiation and tissue homeostasis. Important features of spatial genome conformation in the nucleus are promoter-enhancer contacts regulating gene expression within topologically-associated domains (TADs), short- and long-range interactions between TADs and associations of chromatin with nucleoli and nuclear speckles. In addition, anchoring of chromosomes to the nuclear lamina via lamina-associated domains (LADs) at the nuclear periphery is a key regulator of the radial distribution of chromatin. To what extent TADs and LADs act in concert as genomic organizers to shape the three-dimensional topology of chromatin has long remained unknown. A new study addressing this key question provides evidence of (i) preferred long-range associations between TADs forming TAD "cliques" which organize large heterochromatin domains, and (ii) stabilization of TAD cliques by LADs at the nuclear periphery after induction of terminal differentiation. Here, we review these findings, address the issue of whether TAD cliques exist in single cells and discuss the extent of cell-to-cell heterogeneity in higher-order chromatin conformation. The recent observations provide a first appreciation of changes in 4-dimensional higher-order genome topologies during differentiation.

Keywords: 4D nucleome; Hi-C; LAD; TAD clique; TAD-TAD interaction; genome structural modeling.

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Figures

Figure 1
Figure 1
TAD cliques represent spatial assemblies of heterochromatic TADs from Hi-C data. (A) Higher-order chromatin topology in a mammalian nucleus, highlighting a lamina-associated domain (LAD), topologically-associated domains (TADs) and TAD-TAD interactions. (B) Hi-C contact matrix showing TADs along the diagonal and highlighting some of the long-range TAD-TAD interactions, away from the diagonal (black frames); shown here for a region of chromosome 3 in human adipose MSCs. (C) Graph representation of a clique where four vertices (or TADs; A,C,E,F) all interact pair-wise in the fictive incidence matrix (red cells in the matrix, red edges in the graph). Vertices B and D, respectively, interact with vertices C and E only (blue cells in the matrix, blue edges in the graph) and do not belong to the clique. The clique shown here is of size k = 4. (D) Chrom3D structural models of an MSC nucleus. Models show all chromosomes as a continuous chain of beads (TADs) labeled differently (left) and highlight TAD cliques of size 9 on both chromosome 3 homologs (right). Note the variation in TAD proximity in both modeled chromosomes. (E) Representative FISH image of six TADs in a clique (green probes; chromosome 1) and five TADs not in clique (red probes; chromosome 5) (see Paulsen et al., 2019 for details). Note the absence of strict physical contact between all TADs even when they belong to a clique in the Hi-C data (green probes). Also note the variation in relative TAD distributions between the two sets of homologous chromosomes. Bar, 2 μm. (F) Browser view of A and B compartments, consensus TADs (shown over two lines for clarity), TAD cliques with clique size (number of TADs), LADs, H3K9me3, H3K27me3 and gene expression in undifferentiated adipose MSCs. Sequence data can be accessed at NCBI GEO GSE109924 (compartments, TADs, cliques and LADs), GSM621398 (H3K9me3), GSM621420 (H3K27me3), and GSE60237 (RNA).
Figure 2
Figure 2
Association of TAD cliques with the nuclear periphery. (A) Browser view showing de novo LADs appearing in pre-existing TAD cliques in a B compartment on day 3 of adipose differentiation. Sequence data can be accessed at NCBI GEO GSE109924 and GSE60237. (B) Radial positioning of TAD cliques in the nucleus: model views. Top, differential preferred radial position of a small (pink) and a large (red) TAD clique. Bottom, differentiation repositions a TAD clique toward the nuclear periphery; orange arrow symbolizes differentiation.
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