Final Report Summary - CHROMHERITANCE (Chromosome inheritance from mammalian oocytes to embryos)
One of the most dramatic transitions in biology is the conversion of an egg through fertilisation by sperm to an embryo. In order to generate a healthy embryo, it is critical that the correct set of chromosomes is inherited from the egg. Our work has provided key insights into how this process is controlled in the mouse. We found that the cohesive ties that hold replicated chromosomes together are established in oocytes, the egg precursor cells, during fetal development and are thereafter maintained for months without renewal in the adult mouse. The ties are mediated by the meiotic cohesin complex that is essential for chromosome segregation and production of euploid eggs. However, cohesin abundance on chromosomes decreases with age. The gradual loss of cohesin without functional replacement can potentially explain why egg aneuploidy and trisomic pregnancies like Down's syndrome increase with maternal age.
Fertilisation results in the erasure and resetting of epigenetic chromatin marks of the genomes contributed by egg and sperm. Epigenetic reprogramming is considered to be important to generate a totipotent embryo that has the developmental potential to generate all cell types and a whole organism. We developed a single-cell method that revealed a unique reorganisation of 3D chromatin structure during the egg-to-embryo transition and discovered unexpected differences in chromatin structure between maternal and paternal genomes of the single-cell embryo. The paternal genome is reprogrammed by a poorly understood mechanism of active loss of DNA cytosine methylation. Our work provided genetic evidence that this mechanism involves the breaking and repairing of DNA. Importantly, the single-cell embryo monitors this process through a surveillance mechanism that prevents entry into mitosis until reprogrammed DNA lesions are repaired. Our work implies that this mechanism ensures that DNA break-reprogramming is completed within one cell cycle.
Fertilisation results in the erasure and resetting of epigenetic chromatin marks of the genomes contributed by egg and sperm. Epigenetic reprogramming is considered to be important to generate a totipotent embryo that has the developmental potential to generate all cell types and a whole organism. We developed a single-cell method that revealed a unique reorganisation of 3D chromatin structure during the egg-to-embryo transition and discovered unexpected differences in chromatin structure between maternal and paternal genomes of the single-cell embryo. The paternal genome is reprogrammed by a poorly understood mechanism of active loss of DNA cytosine methylation. Our work provided genetic evidence that this mechanism involves the breaking and repairing of DNA. Importantly, the single-cell embryo monitors this process through a surveillance mechanism that prevents entry into mitosis until reprogrammed DNA lesions are repaired. Our work implies that this mechanism ensures that DNA break-reprogramming is completed within one cell cycle.