A recent paper, released as preprint in biorxiv, has explored long-range interaction patterns and identified TAD cliques that can predict key features of chromatin organisation.
Spatial organisation and packaging of the genome is vital for gene expression regulation and can often be altered in disease. There are multiple processes, such as transcriptional compartmentalisation, DNA loop extrusion and interactions with the nuclear lamina, that can dynamically act on chromatin at multiple levels. In order to understand the underlying organisational principles of 3D genome architecture, multi-scale and multi-scope approaches must be used.
Hi-C matrix analyses have revealed nested levels of high-frequency interactions delineated by relatively abrupt boundaries between them. These are known as topologically associated domains or TADs. TADs are architectural chromatin units that define regulatory landscapes. This suggests their implication in shaping functional chromosomal organisations. Disruption of TAD structures can lead to gene misexpression, which can contribute to developmental defects and cancers. Identifying TAD borders has proven difficult. This is because the identification of TADs strongly relies on the resolution of Hi-C data. Therefore, increasing sequencing depth and resolution can reveal finer patterns of chromatin contacts as well as internal insulation regions.
In this study, researchers explored the properties of TADs engaging in TAD-TAD interactions in four human cell lines from Hi-C data. Their results suggested that TADs that belong to large or small cliques display distinct genomic features. Most significantly, TADs in larger cliques were found to be depleted of convergent CTCF-motifs at their boundaries. This suggests that chromatin loop extrusion involving CTCF cannot explain the formation of these TADs. These cliques also tended to be repressive across cell types, when comparing gene expression, LINE/SINE repeat content and chromatin sub-compartments. Additionally, they were larger in genomic size and less dense.
These findings shed some important light on long-range TAD-TAD interactions. They provide insight into the organisational principles that govern repressive and active domains in the human genome. Spatial organisation is becoming an important field in exploring gene regulation and disease. TAD cliques constitute an interesting chromatin feature for further study.
Image credit: By Design Cells – canva.com