Diving into the mechanisms of genome organization: when transcription factors recruit cohesin
Thanks to international collaborations with teams in Spain and the USA, the researchers have combined genomic, structural and microscopy approaches to better understand how transcription factors reorganize the three-dimensional architecture of chromatin. This study, led by Grégory Fettweis and Franck Dequiedt, reveals how these proteins recruit the cohesin complex to enhancers, key regions that regulate gene expression.
The cohesin complex plays a central role in genome organization, but the mechanisms directing its localization on DNA remained largely unknown. Recent work, including that of the team, suggests that direct interactions between transcription factors and the cohesin-loading complex, formed by NIPBL and MAU2, guide this localization within enhancers.
The researchers identified two groups of LxxLL-type interaction motifs in the NIPBL protein. These motifs are essential for the dynamics of NIPBL, its interaction partners, and the gene expression programs it regulates. One of these clusters enables NIPBL to associate with MAU2, an interaction essential for the stable formation of the NIPBL-MAU2 complex. The other binds specifically to the ligand-binding domains of steroid receptors.
The study particularly focused on the glucocorticoid receptor (GR), a major regulator of many biological processes such as the metabolism or the inflammation. Using interactomic experiments and predictive tools such as AlphaFold2 and molecular docking algorithms, the researchers modelled a GR-NIPBL-MAU2 ternary complex and highlighted its role in controlling GR-dependent gene expression.
Finally, beyond GR, the team shows that many other transcription factors also interact with the NIPBL-MAU2 complex with similar interaction surfaces or unidentified, yet to be explored.
Reference
Transcription factors form a ternary complex with NIPBL/MAU2 to localize cohesin at enhancers.
