NIH Research Festival
During meiotic prophase I (MPI), chromosomal reorganization enables complex events like DNA double-strand break formation and homologous recombination. The most overt change as cells transition from germ cells through MPI is that chromosomes condense into an array of chromatin loops. However, the conversion from interphase chromatin folding to meiotic loops is poorly understood. Using fluorescence-activated nuclei sorting, we isolated precise stages of mouse spermatogenesis and applied in-situ Hi-C to examine genome structure transitions from mitotic to meiotic states and during pre-meiotic homologous pairing.
We found cohesin density decreases as spermatogonia differentiate, hitting a minimum at the onset of the mitotic-to-meiotic transition and resulting in the loss of most chromatin loops. Notably, a comparable chromatin folding intermediate was identified at telophase during mitotic exit. As cells transitioned further towards meiosis, we observed a progressive elevation in cohesin density, accompanied by an increase in loop length. Levels of RAD21, a mitotic cohesin kleisin, declined, while levels of REC8, a meiotic kleisin, escalated during the same period. This suggests an orchestrated cohesin exchange mediates chromatin reorganization during the mitotic-to-meiotic transition, potentially setting the stage for the axis-loop array reconfiguration in MPI.
By conducting Hi-C in hybrid mice, we discovered inter-homolog interactions in all pre-meiotic stages. Interestingly, these interactions were disrupted during meiotic replication and early leptonema. This is consistent with yeast findings, indicating extensive pre-meiotic pairing in male mouse meiosis preceding DSB formation.
Scientific Focus Area: Genetics and Genomics
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