Azim Surani PhD CBE FRS FMedSci, Director of Germline and Epigenomics Research, Member of the Physiology, Development and Neuroscience Department.

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Human germ cell specification and epigenetic programming

What makes a germline cell? We study primordial germ cells (PGCs), precursors to eggs and sperm, in the early embryo. We have established principles for the mechanisms of cell fate determination and epigenetic programming that are widely applicable to human development and disease. Our work on PGC specification shows that SOX17 is the key regulator of human, but not mouse, germ cell fate.

By developing an in vitro model, and with authentic hPGCs from human embryos, we have also established how pluripotent cells gain competence for germ cell fate in human, compared with mouse. These studies reveal important differences between mouse and human development that might impact on other early cell fate decisions.

Whereas SOX17–BLIMP1 apparently initiate the epigenetic programme in early human germline, BLIMP1– PRDM14 play a similar role in mouse germline, resulting in the comprehensive erasure of DNA methylation (except for some resistant loci), X-reactivation and imprints erasure, followed by re-establishment of sperm and oocyte-specific imprints. Because these imprints are gamete-specific and inherited by the subsequent generation, they provide a model for how different sets of epigenetic marks affect the same genome, to result in different patterns of gene expression and development. 

Selected publications:

• Murakami K et al. (2016) NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers. Nature 529: 403–407.

• Tang WWC et al. (2015) A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Cell 161(6): 1453–1467.

• Irie N, Weinberger L, Tang WWC, Kobayashi T, Viukov S, Manor Y, Dietmann S, Hanna JH, Surani MA  (2015) SOX17 is a critical specifier of human primordial germ cell fate. Cell 160, 253-268 

• Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA and Surani MA (2012) Germline DNA demethylation dynamics and imprint erasure through 5-hydoxymethylcytosine. Science, 339, 448-452

• Tang F, Barbacioru C, Bao S, Lee C, Nordman E, Xiaohui W, Lao K, Surani MA (2010) Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-seq analysis. Cell Stem Cell 6 (5-2) 468-478