Towards a predictive model of chromatin 3D organization

Abstract

Architectural proteins mediate interactions between distant regions in the genome to bring together different regulatory elements while establishing a specific three-dimensional organization of the genetic material. Depletion of specific architectural proteins leads to miss regulation of gene expression and alterations in nuclear organization. The specificity of interactions mediated by architectural proteins depends on the nature, number, and orientation of their binding site at individual genomic locations. Knowledge of the mechanisms and rules governing interactions among architectural proteins may provide a code to predict the 3D organization of the genome.

Topologically associated domains: a successful scaffold for the evolution of gene regulation in animals

“…Furthermore, the recent identification of the same diverging arrangement in a highly conserved TAD border that predates the origin of deuterostomes suggests that the crucial importance of CTCF orientation is probably an ancestral genomic feature . However, it is important to note that, in the case of flies, no clear association between looping and TAD borders with CTCF binding site orientation has been identified so far . Furthermore, in the highly compacted Drosophila genome, TADs are much smaller than in mammals (60 kb mean size vs 800 kb) .…”

“…And yet, these species have retained many ancestral microsyntenic pairs, way more than C. elegans . Thus, CTCF could have also been secondarily lost several times in non‐bilaterian lineages, but maintaining long‐range CREs by other means (i.e., evolving novel lineage‐specific architectural proteins such as the ones present in Drosophila ) . However, this seems rather unlikely, suggesting that long‐range regulation could have evolved prior to the origin of bilaterians, in the last common animal ancestor, but that initially these distant chromatin interactions depended on alternative mechanisms or architectural proteins different from CTCF.…”

“…30 However, it is important to note that, in the case of flies, no clear association between looping and TAD borders with CTCF binding site orientation has been identified so far. 51 Furthermore, in the highly compacted Drosophila genome, TADs are much smaller than in mammals (60 kb mean size vs 800 kb). 23 Thus, although the presence of longrange regulatory interactions and TAD-like structures in both flies and deuterostomes are likely indicative of homology, whether self-interacting domains in Drosophila and mammals are truly equivalent is still an open question.…”

Insulator Activities of Nucleosome-Excluding DNA Sequences Without Bound Chromatin Looping Proteins

“…In human and yeast cells, RNA polymerase III-transcribed sequences were also suggested to serve as insulator sequences with similar mechanisms as CTCF binding sequences. [19][20][21][22][23][24][25][26][27][28] Moreover, various protein binding sequences that form chromatin loops by contacting each other and also exhibit insulator activities have been found in various invertebrates. 19,20,[29][30][31][32][33][34] To precisely regulate gene expression, each enhancer associates with promoters only within the same chromatin domain, with each domain divided by insulators.…”

“…[19][20][21][22][23][24][25][26][27][28] Moreover, various protein binding sequences that form chromatin loops by contacting each other and also exhibit insulator activities have been found in various invertebrates. 19,20,[29][30][31][32][33][34] To precisely regulate gene expression, each enhancer associates with promoters only within the same chromatin domain, with each domain divided by insulators. To explain the mechanisms underlying such physically nontrivial limitation of enhancer motion, various models of chromatin dynamics and enhancer-promoter interactions such as the tracking model for DNA binding proteins, looping model based on enhancer-promoter random collision or enhancer scanning, and the topological domain model based on enhancer-promoter random collision have been proposed.…”