Evolution of 3D chromatin organization in metazoan species
Darío G. Lupiáñez
Centro Andaluz de Biología del Desarrollo (CABD), CSIC/UPO/JA, Seville, Spain
Metazoan genomes are organized into topologically associating domains (TADs), which facilitate interactions between regulatory elements and target genes. Disruptions in TADs can drive human disease, including developmental malformations or cancer, but also serve as a substrate for phenotypical adaptation. Despite their functional significance, studies conducted across diverse animal models have revealed remarkable differences in how these domains are formed. In vertebrates, TADs mainly result from a mechanism of loop extrusion, derived from the interplay between the cohesin complex and the insulator protein CCCTC-binding factor (CTCF). Strikingly, in certain invertebrates such as flies, these domains seem to primarily depend on chromatin and transcriptional state, with a less prominent role for CTCF. This discrepancy raises fundamental questions on how the mechanisms of 3D chromatin organization may have evolved.
In this talk, I will provide specific examples on how changes in TAD organization can be associated to the emergence of certain phenotypical traits, as well as on the constraints that this type of domains exerts on genome evolution. Furthermore, I will present our recent efforts in understanding the evolution of CTCF, by performing interspecies functional replacements. These analyses allowed us to uncouple two distinct functions of CTCF: one as a transcriptional regulator and another a mediator of 3D chromatin organization. Our findings also suggest a model where CTCF has played a major role in the evolution of 3D chromatin architecture by shifting its chromatin binding preferences and partners.