Researchers at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London have shown for the first time that, before they can start developing into egg and sperm cells, the embryonic precursors of these cells uniquely reshape the 3D organization of their genetic material. Led by Dr Tien-Chi Huang and Dr Maria Rigau, these insights published in Nature Structural & Molecular Biology could help guide future efforts to create sperm and eggs in the laboratory \u2013 currently one of the biggest barriers to developing new infertility treatments.<\/p>\n
In our cells,\u00a0our\u00a0DNA\u00a0carries\u00a0chemical\u00a0or\u00a0‘epigenetic’\u00a0marks that\u00a0decide how genes will be used in different tissues.\u00a0Yet in\u00a0the\u00a0group of\u00a0specialised cells, known as ‘germ cells’,\u00a0which\u00a0will\u00a0later form sperm and\u00a0eggs,\u00a0these\u00a0inherited\u00a0chemical\u00a0instructions must be erased\u00a0or\u00a0reshuffled\u00a0so development can begin again with a fresh blueprint\u00a0in\u00a0future generations.\u00a0<\/p>\n
This process, known as\u00a0‘epigenetic reprogramming’,\u00a0involves\u00a0wiping and rebuilding chemical marks on DNA\u00a0and reorganising how DNA is packaged inside the cell.\u00a0This reset prepares cells for meiosis \u2013 the cell division that produces sperm and eggs\u00a0by\u00a0halving a germ cell’s\u00a0genetic material, ensuring the fertilized egg has\u00a0the correct number of chromosomes.\u00a0<\/p>\n
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Scientists\u00a0know\u00a0a great deal about which genes turn on and off during\u00a0this transition,\u00a0but\u00a0far less is known about how the genome itself is physically rearranged in three dimensions\u00a0before\u00a0meiosis takes\u00a0place.”<\/p>\n
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Dr Tien-Chi Huang, first author and postdoctoral researcher in the\u00a0Reprogramming and Chromatin group\u00a0at the LMS<\/p>\n
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A unique genetic structure\u00a0emerges<\/p>\n
By studying\u00a0the structure and\u00a0appearance\u00a0of mouse\u00a0germ cells\u00a0under a microscope,\u00a0the\u00a0team\u00a0found\u00a0that\u00a0as\u00a0these cells\u00a0prepare to undergo\u00a0meiosis (around\u00a014.5\u00a0days after fertilization),\u00a0the constricted region of the chromosomes\u00a0\u2013 known as the centromere \u2013\u00a0becomes\u00a0tethered\u00a0to\u00a0the edge of the nucleus.\u00a0Strikingly, this\u00a0phenomenon\u00a0was also visible in\u00a0early germ cells in\u00a0human\u00a0embryos\u00a0at 14\u00a0weeks\u00a0post\u00a0conception.\u00a0<\/p>\n
Using a\u00a0technique called Hi-C analysis, which looks at how DNA is arranged in three dimensions inside the nucleus, the team\u00a0found\u00a0that at this transitional\u00a0point the\u00a0genome’s\u00a0three-dimensional\u00a0organization\u00a0becomes\u00a0less\u00a0structured\u00a0and chromosomes become\u00a0more\u00a0separated inside the nucleus.\u00a0<\/p>\n
“This the first time anyone has seen this\u00a0change in\u00a0chromosome\u00a0conformation\u00a0at this crucial developmental stage, right before meiosis begins,” says Tien-Chi.\u00a0<\/p>\n
Implications\u00a0for infertility\u00a0<\/p>\n
Creating sperm and eggs in the laboratory (in vitro\u00a0gametogenesis)\u00a0remains\u00a0one of the greatest challenges in reproductive biology. To study this process, scientists use primordial germ cell\u2013like cells (PGCLCs), which are lab-generated cells derived from\u00a0embryonic\u00a0stem cells that mimic the embryo’s earliest reproductive cells.\u00a0However, these PCGLCs\u00a0often\u00a0fail\u00a0to\u00a0complete all the\u00a0steps of meiosis, making it\u00a0difficult\u00a0to create functional sperm and eggs\u00a0in\u00a0petri\u00a0dishes.\u00a0<\/p>\n
After\u00a0studying the process in germ cells from the embryos, the team\u00a0studied\u00a0lab-generated\u00a0mouse\u00a0PCGLCs\u00a0to see\u00a0if\u00a0the\u00a0centromeres\u00a0migrated to the periphery of the nucleus\u00a0in vitro\u00a0too,\u00a0but\u00a0they did not see\u00a0the same phenomenon.\u00a0<\/p>\n
“The presence of this\u00a0chromosome conformation\u00a0in\u00a0embryonic germ\u00a0cells, but not lab-grown cells, suggests that\u00a0this structural change\u00a0could be\u00a0required for meiosis to proceed properly,\u00a0and could\u00a0explain why\u00a0meiosis\u00a0is so difficult to recreate outside the body,” says Tien-Chi, “but we need to do more work to fully characterise\u00a0the process\u00a0before we can say for sure.”\u00a0<\/p>\n
“Our study has uncovered a\u00a0previously\u00a0unknown\u00a0and frankly very surprising restructuring of genome architecture that occurs in\u00a0developing germ cells,\u00a0which\u00a0we believe is critical for a successful execution of meiosis,”\u00a0says Professor Petra\u00a0Hajkova, senior author and Head of the Reprogramming and Chromatin group\u00a0at the\u00a0LMS. “Our findings will not only amend the current textbook knowledge but will\u00a0be critical for our efforts to recapitulate meiosis and hence\u00a0complete gamete development\u00a0in vitro.”\u00a0<\/p>\n
This\u00a0new framework for improving\u00a0in vitro\u00a0gametogenesis\u00a0may help researchers create functional sperm and eggs outside the body in the future, which\u00a0could eventually lead to\u00a0new treatments for infertility and may even help same-sex couples have genetically related children.\u00a0<\/p>\n
“This work was a collaboration between three fantastic teams co-localised at the LMS. My big “thank you” goes to Juanma\u00a0Vaquerizas, Mikhail Spivakov and their teams for a very enjoyable scientific tour de force,” concludes Petra.\u00a0<\/p>\n
This study was funded by\u00a0the Medical Research Council,\u00a0the European Research Council, the Academy of Medical Sciences and\u00a0the Department of Business,\u00a0Energy\u00a0and Industrial Strategy.\u00a0<\/p>\n
Source:<\/p>\n
Medical Research Council (MRC) Laboratory of Medical Sciences<\/a><\/p>\n Journal reference:<\/p>\n