Topologically Associating Domains: An invariant framework or a dynamic scaffold?

Abstract

Metazoan genomes are organized into regions of topologically associating domains (TADs). TADs are demarcated by border elements, which are enriched for active genes and high occupancy architectural protein binding sites. We recently demonstrated that 3D chromatin architecture is dynamic in response to heat shock, a physiological stress that downregulates transcription and causes a global redistribution of architectural proteins. We utilized a quantitative measure of border strength after heat shock, transcriptional inhibition, and architectural protein knockdown to demonstrate that changes in both transcription and architectural protein occupancy contribute to heat shock-induced TAD dynamics. Notably, architectural proteins appear to play a more important role in altering 3D chromatin architecture. Here, we discuss the implications of our findings on previous studies evaluating the dynamics of TAD structure during cellular differentiation. We propose that the subset of variable TADs observed after differentiation are representative of cell-type specific gene expression and are biologically significant.

Keywords: 3D architecture; CTCF; TAD; architectural proteins; chromatin; differentiation; epigenetics; heat shock; insulators.

Figure 1.

TAD dynamics in response to temperature stress and cellular differentiation. Cartoon schematic illustrating the non-random chromatin interactions occuring along a chromosome, resulting in enrichments that have been named TADs and subTADs. The strength of chromatin interactions is depicted in red. The directionality of chromatin interactions is at least partially regulated by the orientation of CTCF sites in the genome, and has been shown to correlate with both subTAD and TAD borders. A visual depiction of the TAD border strength, a quantitative analysis of the ratio of inter-TAD and intra-TAD interactions surrounding the locus, is shown in green. Temperature stress: After heat shock, a dramatic restructuring of the 3D architecture occurs with a striking increase in inter-TAD interactions. Variability is observed in the architecture of both subTADs (shown in blue) and TADs (depicted by changes in border strength). Differentiation: During differentiation, cell-type specific enhancer-promoter interactions result in alterations in the subTAD structure (shown in blue). We propose that regions of highly variable subTAD structure also correspond to regions of variable TAD structure (illustrated by the increase in border strength), while regions of low variability in subTADs likely correspond to conserved TADs between cell types.