Completed Genetics & Molecular Biology Pregnancy, Children & Inherited Conditions

Principles of human development and germ cell program

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £2.8M
Period Jan 2018 — Dec 2023

In plain English

AI plain-English summary

Human embryos begin to set aside their future eggs or sperm just days after conception, at a stage called gastrulation, when the body’s basic tissues first take shape. This project aims to map exactly how a handful of cells become primordial germ cells—the precursors to sperm and eggs—and how those cells then wipe clean most of their DNA methylation, a chemical mark that records a cell’s history. The researchers will use donated embryos, lab-grown embryo models, and cells from aborted fetuses to watch this process unfold. They also want to understand why some stretches of DNA resist this erasure, and whether those resistant regions have been repurposed to act as control switches for other genes. If so, those switches could influence brain development and neurological diseases. This is fundamental science: it does not aim to produce a therapy or diagnostic tomorrow. But understanding how the germline resets its epigenetic state could eventually improve regenerative medicine, explain why certain disorders run in families without a clear genetic cause, and clarify how early development shapes lifelong health.

View original technical description
Specification of human primordial germ cells (hPGCs) occurs around gastrulation, a critical juncture when the specification of the primary somatic lineages also occurs. In combination with human preimplantation embryos, in vitro models and hPGCs from aborted fetuses, our objective is to elucidate the origin and properties of the early human germline. For the mechanism of the hPGC fate, we will use experimental models that simulate early human development. We aim to investigate how cells gain competence for germ cell fate, and then respond to combinatorial effects of the critical transcription factors, which induce hPGC specification. Altogether, this study will reveal the organisation of the very early human embryo, and mechanisms of hPGC and somatic outcomes, which is essential for advances in regenerative medicine. Following hPGC specification, epigenetic resetting of the early human germline leads to extensive erasure of DNA methylation and epimutations in response to the critical regulators of chromatin organisation and nuclear architecture towards the epigenetic ground state. Some conserved resistant loci ('escapees') evade reprogramming. We will explore if some escapees have been exapted to function as regulatory elements. If so, this may have a crucial influence on human development, including brain development and neuronal diseases.

View the original record at the funder ↗

Researchers

Azim Surani (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Development of human primordial germ cells towards the onset of sperm and egg differentiation in a novel model culture system
Human germline in vitro models for development and the epigenetic program
Developmental roadmap of primordial germ cells in humans and pigs
Deciphering mechanisms driving human primordial germ cell development using stem cell-based model systems
Defining the epigenetic principles that instruct the development of human embryos

Original classification

Investigator Award in Science

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