The role of transcription in shaping the spatial organization of the genome

Abstract

The spatial organization of the genome into compartments and topologically associated domains can have an important role in the regulation of gene expression. But could gene expression conversely regulate genome organization? Here, we review recent studies that assessed the requirement of transcription and/or the transcription machinery for the establishment or maintenance of genome topology. The results reveal different requirements at different genomic scales. Transcription is generally not required for higher-level genome compartmentalization, has only moderate effects on domain organization and is not sufficient to create new domain boundaries. However, on a finer scale, transcripts or transcription does seem to have a role in the formation of subcompartments and subdomains and in stabilizing enhancer-promoter interactions. Recent evidence suggests a dynamic, reciprocal interplay between fine-scale genome organization and transcription, in which each is able to modulate or reinforce the activity of the other.

Figure 1. Two main principles of chromosome organisation.

(A) Compartments are formed by aggregation of multiple domains with similar biochemical or functional properties. The two most prominent compartments are heterochromatin (blue, often positioned near the nuclear lamina) and euchromatin (red). (B) Self-association of heterochromatin and euchromatin domains is detectable as long-range contacts in Hi-C maps. (C) Cartoon illustrating the partitioning of the genome into TADs (different shades of grey), which have primarily intradomain contacts and fewer inter-domain contacts. (D) Cartoon representation of part of a Hi-C map, with intra-TAD contacts depicted as a grey scale. TADs are often nested structures.

Figure 2. Gene relocation from peripheral heterochromatin to internal euchromatin.

(A) Active genes are typically located in the nuclear interior, while a subset of inactive genes is located in the heterochromatin layer at the nuclear lamina. (B) Binding of a strong transcription activator can relocate a gene to the nuclear interior. (C) Tethering of a peptide with chromatin decondensing activity can relocate a gene to the nuclear interior without transcription activation. (D) Activation of a nearby lncRNA gene can relocate a flanking coding gene to the nuclear interior.

Figure 3. Alternative mechanisms of TAD boundary formation.

(A) TADs may be the result of loop extrusion by cohesin complexes (green rings). One TAD may consist of multiple loops that are dynamically formed and resolved. CTCF, when bound in the correct orientation, could act as a “road block” that stops progression of loop extrusion, thereby creating a TAD border. (B) Similarly, active genes, the transcription pre-initiation complex, or a chromatin mark associated with it, could block loop extrusion.

Figure 4. Properties of TAD borders in different cell types and species.

CTCF, active promoters, and associated chromatin marks are found at TAD borders to varying degrees. + denotes low level (<25%), ++ high level (~60%), +++ the vast majority, or - not present (0%). The references are indicated.

Figure 5. Compartmentalization of active and inactive chromatin.

Cartoon illustrating self-association, which may occur at multiple scales: both at the level of large domains (top panel), and at the level of individual genes (bottom panel). Red shades: compartment A (euchromatin); blue shades: compartment B (heterochromatin, LADs).