A study led by scientists at the Universitat Autònoma de Barcelona (UAB) has demonstrated that alterations in the 3D organisation of the genome can affect fertility.
The genome is tightly organised within the cell nuclei. In recent years, researchers have become more aware of the role that 3D genome organisation has in regulating gene expression. Chromatin structure establishes the limits of gene-regulatory domains. Consequently, disturbances of this domain architecture due to genome reshuffling (e.g. inversion, fusions or indels) can alter gene regulation. This is because shifting domain boundaries can expose genes to novel regulatory environments.
Evidence has found that indels and inversions can alter interactions between topological associated domains (TADs), which can lead to oncogene activation and novel gene functions. However, the impact of balanced chromosomal rearrangements, such as Robertsonian (Rb) fusions, are less explored. Rb fusions are the most common chromosomal rearrangement in nature. They are also linked to recurrent miscarriages, infertility and aneuploid offspring in humans.
Germ cells represent a unique cell model to study the impact of chromosomal fusions. They have sequential developmental stages that involve tightly regulated chromosomal movement and chromatin remodelling. Until now, the impact of large-scale genome reshuffling on the 3D genome topology in germ cells and its implications for recombination were unknown.
3D genome and fertility
In this study, published in Nature Communications, researchers explored how genome folding and recombination landscapes in mouse germline cells are affected by chromosomal fusions. They combined chromosome conformation capture with SNP genotyping and analysis of crossover events.
The group found that chromosomal fusions altered the nuclear architecture during meiosis. This impacted both the dynamics of genome organisation during formation of gametes and recombination. They detected that chromosomal rearrangements affected chromosome folding within the nucleus of the germ cells. As a result, this altered the pairing of homologous chromosomes and subsequent meiotic recombination.
Overall, these results pave the way for new investigations into the genetic mechanisms involved in infertility. In addition, understanding the mechanisms regulating the structure and function of the genome during gamete formation is fundamental as it is deregulated in many disorders, such as infertility and Down syndrome.
Image credit: By Girolamo Sferrazza Papa – canva