Germ Cell Development: 3D Genome Restructuring Key to Infertility Treatment?
- Researchers have discovered a unique reshaping of genomic architecture in embryonic cells as they prepare to become sperm and eggs.
- Maria Rigau at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London, details how germ cells undergo a dramatic reorganization of their DNA’s three-dimensional structure.
- Epigenetic reprogramming is a fundamental process where chemical marks on DNA – influencing gene activity – are erased and rebuilt.
Researchers have discovered a unique reshaping of genomic architecture in embryonic cells as they prepare to become sperm and eggs. This previously unknown process, occurring before the onset of meiosis, could hold the key to improving in vitro gametogenesis – the laboratory creation of sperm and eggs – and ultimately offer new avenues for treating infertility.
The study, led by Dr. Tien-Chi Huang and Dr. Maria Rigau at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London, details how germ cells undergo a dramatic reorganization of their DNA’s three-dimensional structure. This restructuring is essential for the epigenetic reprogramming that wipes clean the cellular memory of the developing germ cells, preparing them to contribute genetic material to the next generation.
Epigenetic reprogramming is a fundamental process where chemical marks on DNA – influencing gene activity – are erased and rebuilt. This reset is crucial for ensuring the correct genetic information is passed on during meiosis, the cell division that halves the chromosome number to create sperm and eggs. While scientists have mapped the genes that switch on and off during this transition, the physical rearrangement of the genome itself remained largely a mystery until now.
Centromere Tethering and Genome Disorganization
Using microscopic observation of mouse germ cells, the researchers found that as these cells approach meiosis (around after fertilization), the centromeres – the constricted regions of chromosomes – become tethered to the edge of the cell nucleus. Remarkably, this phenomenon was also observed in early germ cells from human embryos at post-conception, suggesting a conserved mechanism across mammals.
Further analysis using Hi-C analysis, a technique that maps the three-dimensional arrangement of DNA within the nucleus, revealed that at this critical juncture, the genome’s overall structure becomes less organized. Chromosomes become more separated within the nucleus, indicating a significant shift in how DNA is packaged and accessed.
“This is the first time anyone has seen this change in chromosome conformation at this crucial developmental stage, right before meiosis begins,” said Dr. Huang, a postdoctoral researcher in the Reprogramming and Chromatin group at the LMS.
Implications for In Vitro Gametogenesis
Creating functional sperm and eggs in the laboratory has proven to be a major hurdle in reproductive biology. Researchers often utilize primordial germ cell–like cells (PGCLCs) – lab-generated cells derived from embryonic stem cells – to mimic the earliest stages of germ cell development. However, these PGCLCs frequently fail to complete all the steps of meiosis, hindering the creation of viable gametes.
The team investigated whether the centromere migration observed in embryonic germ cells also occurred in lab-grown PGCLCs. Surprisingly, they did not observe the same phenomenon in vitro. This suggests that the observed structural change may be a necessary step for proper meiotic progression and could explain the difficulties in recreating meiosis outside the body.
“The presence of this chromosome conformation in embryonic germ cells, but not lab-grown cells, suggests that this structural change could be required for meiosis to proceed properly, and could explain why meiosis is so difficult to recreate outside the body,” Dr. Huang explained. “But we need to do more work to fully characterize the process before People can say for sure.”
Professor Petra Hajkova, Head of the Reprogramming and Chromatin group at the LMS, emphasized the significance of the findings. “Our study has uncovered a previously unknown and frankly very surprising restructuring of genome architecture that occurs in developing germ cells, which we believe is critical for a successful execution of meiosis,” she said. “Our findings will not only amend the current textbook knowledge but will be critical for our efforts to recapitulate meiosis and hence complete gamete development in vitro.”
This discovery offers a new framework for improving in vitro gametogenesis, potentially paving the way for the creation of functional sperm and eggs in the lab. This could lead to novel treatments for infertility and even enable same-sex couples to have genetically related children.
The research was a collaborative effort involving teams co-located at the LMS, with contributions from Juanma Vaquerizas and Mikhail Spivakov and their respective teams.
This study was funded by the Medical Research Council, the European Research Council, the Academy of Medical Sciences, and the Department of Business, Energy and Industrial Strategy.