Embryos make sex cells in their first two weeks

Producing the next generation of life is already occuring in an embryo in its own first weeks. Human primordial germ cells — which give rise to sperm or egg cells — are present in embryos by their second week of development.

Research carried out between laboratories run by Wolf Reik, and Peter Rugg-Gunn in the Epigenetics research program at Babraham Institute, Cambridge, UK, investigate early stages of primordial germ cell — egg and sperm cell — development in order to generate human like germ cells from mice germ cells.

They reported their success in the latest issue of Developmental Cell, where they explain how they generated 'lookalike' human germ cells from mouse cells. The significance of their work is finding out what happens at the epigenetic level that influences cell differentiation.

Epigenetics refers to reversible modifications made to DNA that don't affect the DNA sequence, but alter how genes are 'read' and therefore influences how proteins are created. Specific marks on a cell which are made epigenetically — meaning from influences ouside of that cell's internal DNA blueprint — specifies a cell's functional identity. Epigenetic controls makes cells different from each other. For example, a skin cell is not a liver cell, even though both contain the same DNA in their chromosomes.

The development of primordial germ cells (sperm and eggs) happens through significant epigenetic remodelling of their original gene 'blueprint.' Primordial germ cells must 'forget' their pre-programmed instructions, create new blueprints and mature into sperm or eggs.

Creating and analysing 'lookalike' primordial germ cells helps scientists identify the (1) early stages of germ cell development and (2) how embryos regulate their developmental timing.

Up to now, developmental insight has been limited due to the difficulty in obtaining germ cells from early embryos just weeks after fertilization. The ability to generate human 'lookalike' primordial germ cells will significantly impact human fertility studies as well.

"Our method establishes a reliable system that can be used to explore early stages of epigenetic reprogramming in primordial germ cell-like cells and how they are regulated in the generation of reproductive cells."

Ferdinand von Meyenn PhD, postdoctoral research fellow (Reik lab), Epigenetics Research, Babraham Institute, lead researcher and first author on the paper.

Continues Professor Wolf Reik, FRS Fellowship of the Royal Society, Molecular Biologist, Head of the Epigenetics research program, the Babraham Institute; Professor of Epigenetics, University of Cambridge; associate faculty, Sanger Institute:

"Charting different developmental timings in the early reprogramming events of the human and mouse-derived cells gives us the first mechanistic insight into how such events are regulated — which is tremendously exciting.

"The next steps are to capture what happens in the later stages of primordial germ cell development and related epigenetic events. In particular, this new method will allow us to answer questions regarding transgenerational epigenetic inheritance in humans."

Abstract Highlights
•Defined specification of human in vitro PGCLCs from naive ESCs
•Human and mouse epigenetic germline reprogramming tempo differs significantly
•Demethylation-resistant regions are enriched in TEs and repressive chromatin marks
•Mouse in vitro PGCLCs show expression of transposon-derived piRNAs

Summary
Primordial germ cell (PGC) development is characterized by global epigenetic remodeling, which resets genomic potential and establishes an epigenetic ground state. Here we recapitulate PGC specification in vitro from naive embryonic stem cells and characterize the early events of epigenetic reprogramming during the formation of the human and mouse germline. Following rapid de novo DNA methylation during priming to epiblast-like cells, methylation is globally erased in PGC-like cells. Repressive chromatin marks (H3K9me2/3) and transposable elements are enriched at demethylation-resistant regions, while active chromatin marks (H3K4me3 or H3K27ac) are more prominent at regions that demethylate faster. The dynamics of specification and epigenetic reprogramming show species-specific differences, in particular markedly slower reprogramming kinetics in the human germline. Differences in developmental kinetics may be explained by differential regulation of epigenetic modifiers. Our work establishes a robust and faithful experimental system of the early events of epigenetic reprogramming and regulation in the germline.

Authors: Ferdinand von Meyenncorrespondence, Rebecca V. Berrens, Simon Andrews, Fátima Santos, Amanda J. Collier, Felix Krueger, Rodrigo Osorno, Wendy Dean, Peter J. Rugg-Gunn, Wolf Reik

DOI: http://dx.doi.org/10.1016/j.devcel.2016.09.015

Open access funded by Wellcome Trust

Keywords:
primordial germ cell, PGC, PGC-like cell, chromatin, epigenetic resetting, epigenetic reprogramming, PGC specification, DNA methylation, piRNA, Piwi-interacting RNA

This research was funded by the Biotechnology and Biological Sciences Research Council, The Wellcome Trust, the EU BLUEPRINT Consortium and the EpiGeneSys FP7 EC-funded Network of Excellence. Ferdinand von Meyenn was funded by a Postdoctoral Fellowship of the Swiss National Science Foundation.
Return to top of page

Oct 19, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Epigenetic influences on DNA methylation can change protein function and cell identity.
BLUE histones spool chromosomes into tight bundles to fit within the cell nucleus. YELLOW
epigenetic markers affect how tight or loose is the wound DNA - and thus protein production.
Image Credit: Imperial College, London, United Kingdom