3D genome characterisation of human spermatogenesis

• Applicant: Professor Dr. Juan M. Vaquerizas
• Subject Area: Reproductive Medicine, Urology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329621271

The three-dimensional organization of chromatin plays a crucial role during gametogenesis and early embryonic development, since it is intimately intertwined with the dramatic changes in epigenetic programs in these cells as well as meiotic recombination. Recent studies have examined the changes of the 3D genome during spermatogenesis in mice and rhesus monkey, highlighting a complex transition of changes in chromatin organization for pachytene spermatocyte cells. However, whether similar transitions occur in humans is not known. This is of particular importance since mature sperm have different chromatin organisation than that found in mouse of rhesus monkey. As a result, we currently lack an understanding of how changes in chromatin conformation are related with meiotic recombination cross-over events in human and how these impact human fertility.My laboratory has pioneered the development of low input techniques to examine chromatin conformation and the characterisation of dynamic changes in the 3D genome during gametogenesis and early embryonic development in mammals. In particular, through a CRU326 Pilot Project, we have characterised the three-dimensional chromatin organisation of human sperm, recapitulating a recent observation that mature sperm in humans, as opposed to other mammals and primates, lacks a defined chromatin organisation. Here, building upon these developments, we will now use beyond state-of-the art genomic techniques to dissect at a single-cell resolution level the dynamics of the three-dimensional organisation of chromatin during human spermatogenesis, the gene regulatory networks that drive the differentiation process, and how these are affected in patients with balanced translocations.The characterisation of the three-dimensional chromatin organisation and the associated gene regulatory networks during human spermatogenesis will provide the basis for understanding how the organisation of the genome and processes such as recombination are connected. In addition, our results will constitute an invaluable regulatory atlas that will inform clinical decisions regarding the role of mutations and structural variation in male infertility.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 326: Male Germ Cells: from Genes to Function