A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development
Walfred W C Tang1, Sabine Dietmann2, Naoko Irie1
1Wellcome Trust Cancer Research UK Gurdon Institute, Tennis Court Road, University of Cambridge, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, Downing Street, University of Cambridge, Cambridge CB2 3EG, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Tennis Court Road, University of Cambridge, Cambridge CB2 3EG, UK.
Cell
|June 6, 2015
Summary
Human germline epigenome reprogramming is unique, with specific gene networks driving DNA demethylation and chromatin changes. Some elements resist demethylation, suggesting potential for transgenerational epigenetic inheritance impacting development and disease.
Area of Science:
- Developmental Biology
- Epigenetics
- Genomics
Background:
- Epigenetic reprogramming in human primordial germ cells (hPGCs) is essential for development.
- Understanding the unique transcriptional and epigenetic landscape of hPGCs is crucial.
Purpose of the Study:
- To elucidate the transcriptional network governing hPGCs.
- To characterize the dynamic epigenetic reprogramming, including DNA demethylation, in early human germline development.
Main Methods:
- Base-resolution methylome analysis of in vivo hPGCs.
- Analysis of gene expression patterns, including pluripotency and somatic specifier genes.
- Investigation of DNA methylation pathways and TET-mediated hydroxymethylation.
Main Results:
- Human PGCs exhibit a distinct transcriptional program with co-expression of somatic and pluripotency genes (TFCP2L1, KLF4), regulated by SOX17 and BLIMP1.
- Comprehensive germline DNA demethylation occurs progressively in hPGCs (weeks 5-7), alongside chromatin reorganization, X reactivation, and imprint erasure.
- Certain retroelements (e.g., SVA) and disease-associated loci remain methylated, indicating incomplete demethylation and potential for epigenetic inheritance.
Conclusions:
- The unique transcriptional network in hPGCs drives extensive epigenetic reprogramming, crucial for germline development.
- Incomplete demethylation at specific loci suggests a mechanism for transgenerational epigenetic inheritance with potential phenotypic consequences for development and disease.
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