The primary objective of our research is to elucidate the mechanism of primordial germ cell (PGC) specification, and to investigate the mechanism of extensive epigenetic reprogramming in early germ cells, and by the maternally inherited factors in oocytes. Building on our previous work on germ cell determinants, we aim to resolve comprehensively the molecular foundations of specification of the mammalian germ cell lineage. Specification of PGCs is accompanied by the repression of the somatic programme, and epigenetic modifications that erase the epigenetic memory of their trajectory towards the somatic fate, while restoring an underlying pluripotency. Whereas a repressive complex maintains unipotency of germ cells, dedifferentiation of unipotent PGCs to pluripotent stem cells in vitro is accompanied by the reversal of the PGC specification process. Early germ cells also exhibit unprecedented epigenetic reprogramming, genome-wide DNA demethylation and chromatin remodelling, which are essential towards the establishment of totipotency. These events together with the maternal inheritances of genetic and epigenetic regulators in oocyte are critical towards the establishment of the pluripotent state. We are gathering insight into the mechanisms involved, and continuing to identify the key factors that are crucial at these times. We are interested in exploiting the knowledge gained from studies on germ cells by creating in vitro models for induced epigenetic reprogramming, and using these models towards attempts at rejuvenation of somatic cells.

Mouse germ line cycle with the origin of primordial germ cells and pluripotent stem cells. Epigenetic changes in ganadal PGCs include genome-wide DNA demethylation and chromatin remodelling. Maternal inheritance of epigenetic modifiers in the zygote is critical for the establishment of the pluripotent state.

Overview of epigenetic reprogramming in early germ cells following PGC specification.

Plain English:
Germ cells, the precursors of sperm and eggs, are immortal in the sense that they generate a whole organism upon fertilisation and through them provide an enduring link between all generations, while the body cells perish with each individual. We specifically aim to discover how cells, and indeed any cell, could be converted into a germ cell. Furthermore, we are investigating their unique properties, which confer the immortal state on germ cells. Detailed understanding of the mechanism involved will be valuable for the detection and eradication of immortal cancer cells. This knowledge will also be important for manipulating stem cells and adult cells for the repair and rejuvenation of diseased body tissues, and for the discovery of new therapeutic agents that can prevent or reverse the trend in ageing tissues towards debilitating diseases such as Alzheimer’s and heart disease.

Selected publications:

• Surani MA and Hajkova P (2010) Epigenetic reprogramming of mouse germ cells towards totipotency. Cold Spring Harbor Symposium on Nuclear Organisation and Function,Volume LXXV

• Hajkova P, Jeffries SJ, Lee C, Miller N, Jackson SP, Surani MA (2010) Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway Science 329,78-82

•Tang F,Barbacioru C,Bao S,Lee C,Nordman E,Wang X, 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, 468-478

• Bao S,Tang F, Li X, Hayashi K, Gillich A, Lao K, Surani MA (2009) Epigenetic reversion of postimplantation epiblast to pluripotent embryonic stem cells. Nature 461, 1292-1295

Mouse E7.5 embryo with founder PGCs detected by Stella-GFP reporter (Surani, 2010)