An Isochore Framework Underlies Chromatin Architecture

Abstract

A recent investigation showed the existence of correlations between the architectural features of mammalian interphase chromosomes and the compositional properties of isochores. This result prompted us to compare maps of the Topologically Associating Domains (TADs) and of the Lamina Associated Domains (LADs) with the corresponding isochore maps of mouse and human chromosomes. This approach revealed that: 1) TADs and LADs correspond to isochores, i.e., isochores are the genomic units that underlie chromatin domains; 2) the conservation of TADs and LADs in mammalian genomes is explained by the evolutionary conservation of isochores; 3) chromatin domains corresponding to GC-poor isochores (e.g., LADs) show not only self-interactions but also intrachromosomal interactions with other domains also corresponding to GC-poor isochores even if located far away; in contrast, chromatin domains corresponding to GC-rich isochores (e.g., TADs) show more localized chromosomal interactions, many of which are inter-chromosomal. In conclusion, this investigation establishes a link between DNA sequences and chromatin architecture, explains the evolutionary conservation of TADs and LADs and provides new information on the spatial distribution of GC-poor/gene-poor and GC-rich/gene-rich chromosomal regions in the interphase nucleus.

Fig 1. Heat map of chromatin interactions and isochores map of mouse chromosome 17.

(A). The heat map of chromatin interactions in mouse chromosome 17 (from [8]) is compared with the corresponding compositional profile (drawn from mm 10 genome assembly using a sliding window of 300 Kb and the program of [24]). Isochore families L1 to H3, characterized by increasing GC levels are defined according to the “fixed” boundaries between isochore families (see Table A in S1 File) and are represented in different colors, deep blue, light blue, yellow, orange and red, respectively; the multicolored vertical bars on the top right indicate GC levels that correspond to the compositional boundaries among isochore families. The self-interactions along the diagonal, as well as the interactions along the two major axes, correspond to short isochore blocks or to individual isochores, as stressed by lines through the coinciding boundaries of TADs (blue and broken black lines correspond to GC-poor and GC-rich isochores or isochore blocks, respectively; not all lines were drawn to avoid readability problems). Interactions corresponding to GC-poor regions are also seen in domains corresponding to other GC-poor regions even when located far away on the chromosomes, the intensity of such interactions decreasing, however, with distance. In the case of interactions corresponding to GC-rich isochores, much weaker signals are present outside the diagonal, an indication of more localized interactions. Note that mouse chromosome 17 is an acrocentric chromosome and that the centromeric sequences correspond to the region near the origin of the Megabase (Mb) scale. Unless otherwise stated, all the interaction maps presented in this article are shown at a 250 Kb resolution and isochores are visualized using a 300 Kb sliding window across chromosomes. (B) The heat map of mouse chromosome 17 is compared at a resolution of 100 Kb with the corresponding isochore profile. Interactions along the diagonal are weaker because split into smaller domains, that reveal fine details. For example, the largest GC-rich region on the chromosome (around 30 Mb) is now resolved into several domains that present a finer correspondence with isochores.

Fig 2. Heat map of chromatin interactions and isochores map of human chromosome 7.

(A) The heat map of chromatin interactions of human chromosome 7 (from [3]) and the corresponding LAD map (from [7]; blue inverted profile under the Megabase axis) are compared with the corresponding compositional profile (using the matched b37 assembly of [3], and the program of [24]). The results are comparable with those of Fig 1A, except that the centromeric repeats (that have been sequenced in this chromosome) do not interact with any other sequence and are responsible for the two orthogonal blank stripes on the heat map. Blue lines correspond to TADs, LADs and inter-LADs. (B). The heat map of chromatin interactions over ~30 Mb of human chromosome 7 is analyzed at a resolution of 50 Kb. In this case a finer correspondence of isochore boundaries with LAD and TAD boundaries can be observed.

Fig 3. Chromatin loops and isochores from a 2.1 Mb region of human chromosome 20.

The chromatin loops from a 2.1 Mb region of human chromosome 20 (Fig 6F from [3]) have been aligned with the corresponding heat map which was used to segment the corresponding DNA sequence into isochores. In this Figure the “extended” isochore ranges of Table A in S1 File were used to assign isochores to families, in order to take care of some minimal trespassings of the 46% GC upper threshold of H1 isochores. Asterisks indicate anomalies in the isochores/domains correspondence (see Text).

Fig 4. Inter-chromosomal interactions and isochores.

The heat maps of chromatin interactions of human chromosomes 7 and 10 (from [3]) are compared with the corresponding compositional and LAD profiles (from [7]). Interactions appear to correspond to GC-rich isochores and inter-LADS and to be widely spread over the two chromosomes. Lines are used to guide the visual inspection of these features.

Fig 5. Evolutionary conservation of TADs and isochores.

(A) The compositional profiles of two syntenic regions located on human chromosome 14 and mouse chromosome 12 (from [3, 8] respectively) are almost mirror images of each other, showing the compositional conservation of syntenic regions in evolution. (B) A comparison of compositional profiles and heat maps (from [3]) of the two syntenic regions from panel A. (C and D) GC levels of 1,348 and 1,358 syntenic regions from mouse (left) and dog (right) are plotted against the GC levels of human isochores.