Complex small-world regulatory networks emerge from the 3D organisation of the human genome

Abstract

The discovery that overexpressing one or a few critical transcription factors can switch cell state suggests that gene regulatory networks are relatively simple. In contrast, genome-wide association studies (GWAS) point to complex phenotypes being determined by hundreds of loci that rarely encode transcription factors and which in- dividually have small effects. Here, we use computer simulations and a simple fitting-free polymer model of chromosomes to show that spatial correlations arising from 3D genome organisation naturally lead to stochastic and bursty transcription as well as complex small-world regulatory networks (where the transcriptional activity of each genomic region subtly affects almost all others). These effects require factors to be present at sub-saturating levels; increasing levels dramatically simplifiies networks as more transcription units are pressed into use. Consequently, results from GWAS can be reconciled with those involving overexpression. We apply this pan-genomic model to predict patterns of transcriptional activity in whole human chromosomes, and, as an example, the effects of the deletion causing the diGeorge syndrome.

Deciphering Multi-way Interactions in the Human Genome

“…The cell-type specific transcription clusters we identified support a role in maintaining cell identity, consistent with prior work on transcriptional hubs or factories [15, 16, 17, 18, 19]. Furthermore, the formation of transcription clusters in the nucleus is consistent with small world phenomena in networked systems [20, 21].…”

“…Exploring multi-way contacts has proven to be a more robust way of capturing how these interactions, packaged into individual transcription clusters, achieve optimal and efficient regulation. Our observations suggest that there is a cell type-specific global formation of transcription clusters that paves navigability within the nucleus, resembling small world architecture [21]. Similar to the behavior of short-path propagation in social networks, transcription clusters act as decentralized nodes that collectively assemble genome-wide loci together through spatially coordinated organization.…”

Predicting genome organisation and function with mechanistic modelling

“…Just as genome-wide association studies have been invaluable to discover new patterns in human genetics, we suggest that these genome-wide mechanistic models will provide an unprecedented resource with which to search for additional missing biophysical principles for chromatin folding. Since models such as HiP-HoP resolve both transcription-related proteins (e.g., RNA polymerases) and chromatin, we can attempt to link structure to transcriptional activity; this was demonstrated using the TF model in [69], which examined the relation between the spatial structure of active domains and gene regulatory networks. In the future, a more detailed treatment, such as the incorporation of LE and chromatin heteromorphicity, could be used to further elucidate the elusive biophysical link between 3D gene structure and transcription.…”

Cluster size determines morphology of transcription factories in human cells

“…Chromatin fibres are modelled as bead-and-spring polymers [9,11,12,[29][30][31][32][33][34][35][36][37][38], where each monomer (diameter σ) represents 3 kbp packed into a 30 nm sphere [9,11,35]. Different TFs (or TF:pol complexes) are modelled as differently-coloured spheres (also with diameter σ) able to bind (when in an "on" state) to cognate sites of the same colour that are scattered along the polymer.…”

“…On the one hand, it is widely believed that TADs remain largely invariant in cells with very different transcriptional programs -which points to little role for transcription in determining structure [5] (for an opposing view, see [6]). On the other hand, clusters of active polymerases -called phaseseparated condensates, hubs, and transcription factories [4,[7][8][9][10] -locally stabilise surrounding clouds of loops, thereby providing an example of a structural unit with a clear functional role.…”