The germ line refers to a lineage of cells spanning many generations of individuals. The germ line is “immortal”, with an unlimited proliferative potential and the ability, after gamete formation and fertilization, to give rise to the ultimate totipotent cell – the zygote.
The germ line is fundamentally different from the soma, being in many organisms segregated at the earliest stages of embryonic development. Although recent work has shown that is possible to derive mammalian germ cells, and even functional gametes, from induced pluripotent stem cells (iPSCs) (Hayashi et al., 2011; Hamazaki et al., 2020), many of the developmental processes responsible for germ line segregation and proliferation, germ cell development and gametogenesis are still unknown or poorly understood.
The uniqueness of germ cell lineage raises several fundamental questions related to hereditary information and recombination, aging and avoidance of senescence, gametogenesis, fertilization and zygote formation, and the biology of the cancer cell. Similar to cancer cells, germ cells have an unlimited proliferative potential and avoid senescence. Tumors are also known to express hundreds of embryonic germ line genes (Bruggeman et al., 2020), which shows a significant regulatory overlap between these two cell types.
Aims and Long-term vision
Our AIM is to better understand why are germ cells unique and what is the regulatory overlap with cancer cells. MORE SPECIFICALLY, our AIM is to define the genetic and epigenetic mechanisms responsible for the regulation of gene expression during female germ cells development, and to understand their contribution for germ line segregation and proliferation, female gametogenesis and oocyte-to-zygote transition. Our working HYPOTHESIS is that the germ cells transcriptome is extremely dynamic, being uniquely regulated during germ line development.
We will focus our work in germ line genes and pathways whose mammalian orthologs are known to be relevant for carcinogenesis. For example, Drosophila Kdm5, sfmbt, Pc, E(z), and trr, whose human homologous genes, respectively KDM5/JARID1, MBTD1, CBX8, EZH2, and KMT2C/MLL3, have been extensively associated to cancer (e.g. Kim and Roberts, 2016; Harmeyer et al., 2017; Gala et al., 2018; Plesa and Sujobert, 2019; Tang et al., 2019; Chan and Morey, 2019)).
To reach our aims, we will take advantage not only of our core expertise in Drosophila melanogaster genetics and live-cell imaging, but also recently optimized state-of-the art transcriptomics approaches (e.g. Native elongating transcript sequencing (NET-seq) and Subcellular RNAseq) and ongoing collaborations with laboratories working with human germ cells. Our goal is to integrate female germ cells differentiation with a genome-wide perspective of the oocyte transcriptome dynamics and subcellular organization. This will provide a unique understanding of oogenesis and give a contribution for a better comprehension of the biology of the cancer cell.