Supervisor: Azim Surani
Co Supervisor: Julie Ahringer
Regulation of the human germline specification and epigenetic re-setting
Recent studies have established the gene regulatory network of human primordial germ cell specification and epigenetic resetting, which indicates significant mechanistic divergence from the mouse. For example, Kruppel-like factor 4 (KLF4) and SOX17 are essential regulators of the human germline, but not in mice. KLF4 expression is also present in the human naive pluripotent stem cells (hESC), but its precise role in the human germline is unclear.
KLF4 ChIP-sequencing data in hESCs indicates binding sties to the vital loci for the primordial germ cell (hPGC) specification, including SOX17, PRDM1, and TFAP2C promoters, and or potential enhancer regions. Accordingly, KLF4 and SOX17 play a critical role in human PGC specification. Preliminary observations suggest that KLF4-SOX17may also initiate the epigenetic program in the human germline. The repression of DNMT3B and the expression of TET2 are amongst the potential candidates. The detection of KLF4 enrichment on the young hominoid-specific transposable elements also indicates a potential contribution to the evolution of gene regulatory networks.
KLF4 has an intrinsically disordered region (IDR), suggesting that this factor is critical for protein-protein interactions. Diverse approaches including biochemical, genetic, high-resolution imaging, biophysical, and molecular approaches combined with bioinformatics, might uncover the mechanistic differences between the regulating of mouse and human PGC specification and development. The proposed project will likely show the unique epigenetic and transcriptional regulation of human PGCs, and the basis for the species-specific divergence between mouse and human germline.
Relevant references:
1. Kobayashi, T., Zhang, H., Tang, W. W. C., Irie, N., Withey, S., Klisch, D., Surani, M. A. (2017). Principles of early human development and germ cell program from conserved model systems.. Nature, 546(7658), 416-420. doi:10.1038/nature22812
2. Irie, N., Weinberger, L., Tang, W. W. C., Kobayashi, T., Viukov, S., Manor, Y. S., Surani, M. A. (2015). SOX17 is a critical specifier of human primordial germ cell fate.. Cell, 160(1-2), 253-268. doi:10.1016/j.cell.2014.12.013
3. Tang, W. W. C., Kobayashi, T., Irie, N., Dietmann, S., & Surani, M. A. (2016). Specification and epigenetic programming of the human germ line.. Nat Rev Genet, 17(10), 585-600. doi:10.1038/nrg.2016.88