Unraveling the mechanisms of chromatin fibril packaging

Abstract

Recent data indicate that eukaryotic chromosomes are organized into Topologically Associating Domains (TADs); however, the mechanisms underlying TAD formation remain obscure. Based on the results of Hi-C analysis performed on 4 Drosophila melanogaster cell lines, we have proposed that specific properties of nucleosomes in active and repressed chromatin play a key role in the formation of TADs. Our computer simulations showed that the ability of "inactive" nucleosomes to stick to each other and the lack of such ability in "active" nucleosomes is sufficient for spatial segregation of these types of chromatin, which is revealed in the Hi-C analysis as TAD/inter-TAD partitioning. However, some Drosophila and mammalian TADs contain both active and inactive chromatin, a fact that does not fit this model. Herein, we present additional arguments for the model by postulating that transcriptionally active chromatin is extruded on the surface of a TAD, and discuss the possible impact of this organization on the enhancer-promoter communication and on the segregation of TADs.

Keywords: chromatin spatial structure; nucleosome; polymer simulations; topologically associating domains; transcription.

Figure 1.

Distribution of the ubi-H2B chromatin mark around TAD borders in 3 Drosophila cell lines. Box-plots show the density of ubiquitylated histone H2B in 20-kb bins located at the same position relative to a TAD boundary, averaged over all TADs. The TAD boundaries were aligned so that the inter-TAD bins were placed to the left of the boundary bin (“0 kb” bin) and TAD bins were placed to the right of the boundary bin. The data on the ubi-H2B mark were downloaded from the modENCODE database and processed as described in ref. .

Figure 2.

Computer simulation of the folding of a linear polymer composed of blocks of “inactive” and “active” nucleosomes. (A) One of the predicted spatial configurations of the polymer arranged as follows: 1000A-100B-(100A-10B)×10-100B-1000A, where A is the “inactive” nucleosomes (green) and B is the “active” nucleosomes (black). The simulation was done using the dissipative particle dynamics (DPD) algorithm, as described in ref. , with the only difference being that the conformation was evaluated during the time of 1×10⁶ DPD steps. (B) Spatial proximity map (distance heat map) of the polymer conformation presented in (A) (note, the scale is in beads). A scheme of the model polymer is presented below the map; blocks of “inactive” and “active” nucleosomes are shown in green and black, respectively.