Striking genomic architecture discovered in embryonic reproductive cells before they start developing into sperm and eggs

(Press-News.org) In our cells, our DNA carries chemical or ‘epigenetic’ marks that decide how genes will be used in different tissues. Yet in the group of specialised cells, known as ‘germ cells’, which will later form sperm and eggs, these inherited chemical instructions must be erased or reshuffled so development can begin again with a fresh blueprint in future generations. 

This process, known as ‘epigenetic reprogramming’, involves wiping and rebuilding chemical marks on DNA and reorganising how DNA is packaged inside the cell. This reset prepares cells for meiosis – the cell division that produces sperm and eggs by halving a germ cell’s genetic material, ensuring the fertilised egg has the correct number of chromosomes. 

“Scientists know a great deal about which genes turn on and off during this transition, but far less is known about how the genome itself is physically rearranged in three dimensions before meiosis takes place,” says Dr Tien-Chi Huang, first author and postdoctoral researcher in the Reprogramming and Chromatin group at the LMS.

A unique genetic structure emerges

By studying the structure and appearance of mouse germ cells under a microscope, the team found that as these cells prepare to undergo meiosis (around 14.5 days after fertilisation), the constricted region of the chromosomes – known as the centromere – becomes tethered to the edge of the nucleus. Strikingly, this phenomenon was also visible in early germ cells in human embryos at 14 weeks post conception.  

Using a technique called Hi-C analysis, which looks at how DNA is arranged in three dimensions inside the nucleus, the team found that at this transitional point the genome’s three-dimensional organisation becomes less structured and chromosomes become more separated inside the nucleus. 

“This the first time anyone has seen this change in chromosome conformation at this crucial developmental stage, right before meiosis begins,” says Tien-Chi. 

Implications for infertility 

Creating sperm and eggs in the laboratory (in vitro gametogenesis) remains one of the greatest challenges in reproductive biology. To study this process, scientists use primordial germ cell–like cells (PGCLCs), which are lab-generated cells derived from embryonic stem cells that mimic the embryo’s earliest reproductive cells. However, these PCGLCs often fail to complete all the steps of meiosis, making it difficult to create functional sperm and eggs in petri dishes. 

After studying the process in germ cells from the embryos, the team studied lab-generated mouse PCGLCs to see if the centromeres migrated to the periphery of the nucleus in vitro too, but they did not see the same phenomenon.   

“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,” says Tien-Chi, “but we need to do more work to fully characterise the process before we can say for sure.” 

“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,” says Professor Petra Hajkova, senior author and Head of the Reprogramming and Chromatin group at the LMS. “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 new framework for improving in vitro gametogenesis may help researchers create functional sperm and eggs outside the body in the future, which could eventually lead to new treatments for infertility and may even help same-sex couples have genetically related children. 

“This work was a collaboration between three fantastic teams co-localised at the LMS. My big “thank you” goes to Juanma Vaquerizas, Mikhail Spivakov and their teams for a very enjoyable scientific tour de force,” concludes Petra. 

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. 

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