Inter-Chromosomal Contact Networks Provide Insights into Mammalian Chromatin Organization

The recent advent of conformation capture techniques has provided unprecedented insights into the spatial organization of chromatin. We present a large-scale investigation of the inter-chromosomal segment and gene contact networks in embryonic stem cells of two mammalian organisms: humans and mice. Both interaction networks are characterized by a high degree of clustering of genome regions and the existence of hubs. Both genomes exhibit similar structural characteristics such as increased flexibility of certain Y chromosome regions and co-localization of centromere-proximal regions. Spatial proximity is correlated with the functional similarity of genes in both species. We also found a significant association between spatial proximity and the co-expression of genes in the human genome. The structural properties of chromatin are also species specific, including the presence of two highly interactive regions in mouse chromatin and an increased contact density on short, gene-rich human chromosomes, thereby indicating their central nuclear position. Trans-interacting segments are enriched in active marks in human and had no distinct feature profile in mouse. Thus, in contrast to interactions within individual chromosomes, the inter-chromosomal interactions in human and mouse embryonic stem cells do not appear to be conserved.     

Clustering of Genes Coding for DNA Binding Proteins in a Regionof Atypical Evolution of the Human Genome

Comparison of the human and mouse genomes has revealed that significant variations in evolutionary rates exist among genomic regions and that a large part of this variation is interchromosomal. We confirm in this work, using a large collection of introns, that human chromosome 19 is the one that shows the highest divergence with respect to mouse. To search for other differences among chromosomes, we examine the distribution of gene functions in human and mouse chromosomes using the Gene Ontology definitions. We found by correspondence analysis that among the strongest clusterings of gene functions in human chromosomes is a group of genes coding for DNA binding proteins in chromosome 19. Interestingly, chromosome 19 also has a very high GC content, a feature that has been proposed to promote an opening of the chromatin, thereby facilitating binding of proteins to the DNA helix. In the mouse genome, however, a similar aggregation of genes coding for DNA binding proteins and high GC content cannot be found. This suggests that the distribution of genes coding for DNA binding proteins and the variations of the chromatin accessibility to these proteins are different in the human and mouse genomes. It is likely that the overall high synonymous and intron rates in chromosome 19 are a by-product of the high GC content of this chromosome.Department of Physiology and Molecular Biodiversity, Institut de Biologia Molecular de Barcelona, CSIC, Jordi Girona 18, 08034 Barcelona, Spain     

Minimalistic 3D chromatin models: Sparse interactions in single cells drive the chromatin fold and form many-body units

Computational three-dimensional chromatin modeling has helped uncover principles of genome organization. Here, we discuss methods for modeling three-dimensional chromatin structures, with focus on a minimalistic polymer model which inverts population Hi-C into single-cell conformations. Utilizing only basic physical properties, this model reveals that a few specific Hi-C interactions can fold chromatin into conformations consistent with single-cell imaging, Dip-C, and FISH measurements. Aggregated single-cell chromatin conformations also reproduce Hi-C frequencies. This approach allows quantification of structural heterogeneity and discovery of many-body interaction units and has revealed additional insights, including (1) topologically associating domains as a byproduct of folding driven by specific interactions, (2) cell subpopulations with different structural scaffolds are developmental stage dependent, and (3) the functional landscape of many-body units within enhancer-rich regions. We also discuss these findings in relation to the genome structure–function relationship.     

Divergence of Mammalian Higher Order Chromatin Structure Is Associated with Developmental Loci

Several recent studies have examined different aspects of mammalian higher order chromatin structure – replication timing, lamina association and Hi-C inter-locus interactions — and have suggested that most of these features of genome organisation are conserved over evolution. However, the extent of evolutionary divergence in higher order structure has not been rigorously measured across the mammalian genome, and until now little has been known about the characteristics of any divergent loci present. Here, we generate a dataset combining multiple measurements of chromatin structure and organisation over many embryonic cell types for both human and mouse that, for the first time, allows a comprehensive assessment of the extent of structural divergence between mammalian genomes. Comparison of orthologous regions confirms that all measurable facets of higher order structure are conserved between human and mouse, across the vast majority of the detectably orthologous genome. This broad similarity is observed in spite of many loci possessing cell type specific structures. However, we also identify hundreds of regions (from 100 Kb to 2.7 Mb in size) showing consistent evidence of divergence between these species, constituting at least 10% of the orthologous mammalian genome and encompassing many hundreds of human and mouse genes. These regions show unusual shifts in human GC content, are unevenly distributed across both genomes, and are enriched in human subtelomeric regions. Divergent regions are also relatively enriched for genes showing divergent expression patterns between human and mouse ES cells, implying these regions cause divergent regulation. Particular divergent loci are strikingly enriched in genes implicated in vertebrate development, suggesting important roles for structural divergence in the evolution of mammalian developmental programmes. These data suggest that, though relatively rare in the mammalian genome, divergence in higher order chromatin structure has played important roles during evolution.