Investigating the role of SMC proteins and CTCF in gene expression by HiP-HoP simulations of degron experiments
The three-dimensional organization of chromatin within the nucleus is highly interconnected with gene expression and crucial for cell function. It has been observed that SMC complexes play a key role in organizing the genome. Indeed, cohesin is able to extrude loops that stop at convergent occupied CTCF binding sites. However, the effect of cohesin and other loop extrusion regulatory factors on the transcriptional regulatory network of the cell has not yet been completely understood.
In this work, we used simulations to investigate the roles played by loop extrusion driven by SMC proteins and regulatory factors such as CTCF and WAPL in shaping chromatin architecture. We also studied their effects on gene expression on a chromosomal scale. To obtain the results, we employed the highly predictive heteromorphic polymer (HiP-HoP) framework, which integrates polymer physics with bioinformatic data, to predict the effect of degrading each of these proteins in turn.
Consistently with previous experimental results, we observe that the average transcriptional activity is not strongly impacted by loop extrusion by SMC proteins. Strikingly, the transcriptional noise (measuring the variability of gene expression in the cell population) is instead strongly affected by the removal of these regulatory factors. From our simulations, we are also able to relate these changes in the transcriptional pattern to the ones in 3D chromosomal and gene structure.
