Cohesin promotes chromosomal looping in one-cell embryos
During the first hours after fertilization, the two separate genomes undergo reprogramming events that function to erase the memory of the differentiated cell type and establish a state of totipotency. Last year, the Tachibana lab could gain important insights into the complexity of genome reorganization occurring during the first hours after fertilization in the one-cell mammalian embryo. Together with an international team, the IMBA researchers developed a novel method to analyze these unique genome architectures, published in Nature last year. They observed for the first time a specialized chromatin “ground state” of the maternal genome that is likely crucial to provide insights into the yet mysterious process of epigenetic reprogramming to totipotency, the ability to give rise to all cell types and form a new organism. In their recent follow-up paper published in EMBO Journal, they applied their new method, single-nucleus Hi-C (snHi-C), to analyze which factors are important for establishing or maintaining 3D chromatin structure.
“We show that cohesin is important for organization of chromatin loops and Topologically Associating Domains (TADs) in zygotic genomes, supporting the hypothesis that genomes are organized by loop extrusion, and that cohesin is required for loop extrusion. Manipulating the life time of cohesin molecules on zygotic chromatin revealed differences in the loop length and compaction of maternal and paternal genomes, providing further evidence that their 3D structures differ. ”, explains Johanna Gassler, VBC PhD student in the Tachibana lab, and first author of the current paper.
Thus, cohesin, a protein complex known for holding sister chromatids together and thus allowing faithful chromosome segregation in meiosis and mitosis, also plays a crucial role in the organization of interphase chromatin. Interestingly, several research teams have been investigating this question in different model systems and with different depletion methods. Together this strengthens the notion that cohesin structures chromosomes through the processive enlargement of loops (loop extrusion).
Our findings provide compelling evidence that cohesin is essential for establishing zygotic genome architecture within hours after fertilization. Our work implies that cohesin-dependent loop extrusion organizes mammalian genomes from the one-cell embryo onwards. The rapid formation of chromatin loops and TADs may be important for regulating the onset of embryonic transcription and promoting a state of totipotency.