Epigenetics and chromatin dynamics in gametes : using yeast spores and advanced proteomics – EpiGam

Classical methods in genetics and biochemistry will be used to analyze different aspects of the organization of spore nucleus, and by extension, their gametes.

Advanced technologies in proteomics will be used. These involve quantitative proteomics, a recent field that has been expending rapidly in recent years. Several approaches will be used in different parts of the program including label-free and isotopic labeling techniques (SILAC). Finally, the use of a yeast model will allow a rapid validation of proteomics results using genetic and biochemical approaches.

This experimental design will allow an exploratory research using the model «yeast spores«. New mechanisms will be transfered in real time to higher eukaryotes, and mouse and human spermatogenesis

This program is now active. We are progressing in the characterisation of chromatin dynamics during gametogenesis. Furthermore, new results may inspire new therapeutic strategies to treat systemic yeast infections.

The realization of this program has prospective implications in fertility care, cancer biology, and regenerative medicine.
The World Health Organization estimates that 80 million people worldwide suffer from infertility. Male factors may be responsible for 20-50% of overall infertility. Most medical research on male infertility focuses on hormonal/genetic disorders, but there is a paucity of research on possible epigenetic causes. Elucidating the dynamics and the organization of chromatin in gametes will generate novel potential diagnostic tools and improve medical options for infertile patients.

On going

The field of epigenetics and chromatin dynamics has been developing exponentially over the last decade. Many molecular mechanisms have been unraveled. However, many aspects of chromatin dynamics remain obscure. In particular, the organization of chromatin in gametes is still poorly understood, and the role of this organization in fertilization and early embryonic development is largely unknown. We propose to develop an innovative and ambitious research program that aims at elucidating chromatin organization and dynamics during male gamete differentiation.

The study of gametogenesis has proven to be technically challenging. My post-doctorate work demonstrated that a simple model, yeast sporulation, shares functional epigenetic similarities with mammalian spermatogenesis. I propose to take advantage of this observation and deploy a new research program, EPIGAM, using yeast sporulation as a powerful model for mammalian spermatogenesis.

The program is divided into two main aims. The first project is a candidate approach to determine the functional role of the protein Bdf1 in yeast spores and of its homologue, Brdt, in sperm. The second project is exploratory and will investigate the dynamics of histone acetylation and associated signaling pathways in gametes. This program combines multi-dimensional approaches using genetic, biochemical, and proteomic techniques.
This research program will be hosted by the group “Exploring the Dynamics of Proteomes”, of the Inserm U1038, directed by Jérôme Garin. The partnership between the candidate and the host laboratory has long-term interests, reinforcing a cooperation between fundamental research and the development of new methodologies in proteomics. EPIGAM will have privileged access to cutting-edge proteomics technology and will further the implementation of advanced proteomics methodologies, especially in quantitative proteomics.
Project management has been carefully planned. Tasks have been well documented, and risk analyses, timelines, deliverables, and milestones are presented. Furthermore, a Scientific Advisory Board has been formed and will regularly evaluate the progress of the program and discuss future perspectives.

The launch of this research program is largely dependant on the success of this application. It requires strong financial support from the ANR, especially in regard to human resources, lab equipment, and lab supplies. Additionally, the candidate is currently applying to the CNRS and Inserm for a position as Chargé de Recherche 2 in the host laboratory.

To conclude, the EPIGAM research program is based on a unique combination of:
- an innovative biological question, with potential implications for fertility care, cancer biology, and regenerative medicine.
- an original biological model, yeast spores, validated by several high profile publications.
- the partners of the program, who integrate their respective expertise in genetics, biochemistry, and proteomics in lower and higher eukaryotes.