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Sequential enhancer state remodelling defines human germline competence and specification.

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Summary

Scientists uncovered key epigenetic factors guiding human primordial germ cell (hPGC) development. SOX17 enhancers and a transcription factor network are crucial for establishing the germline program and hPGC fate.

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Area of Science:

  • Developmental Biology
  • Epigenetics
  • Genomics

Background:

  • Germline-soma segregation is essential for mammalian embryonic development.
  • Understanding human primordial germ cell (hPGC) development requires insights into early epigenetic events.

Purpose of the Study:

  • To elucidate the epigenetic principles governing human primordial germ cell (hPGC) development.
  • To identify key regulatory elements and transcription factors involved in hPGC specification.

Main Methods:

  • Utilized in vivo hPGCs and stem cell models simulating gastrulation.
  • Employed CRISPR activation for targeted cis-regulatory element manipulation.
  • Analyzed enhancer activity and transcription factor networks.

Main Results:

  • Mesendoderm enhancer remodeling transiently confers hPGC fate competence.
  • Reducing OTX2 expression promotes hPGC fate.
  • SOX17 and TFAP2C activate core germline program enhancers, including PRDM1, POU5F1, and NANOG.
  • SOX17 enhancers are critical for germline competence circuitry.
  • CRISPR activation of cis-regulatory elements is sufficient for hPGC specification.

Conclusions:

  • Established the epigenetic basis of hPGC development, highlighting SOX17 enhancers and a germline transcription factor network.
  • Revealed a regulatory network underlying germline competence and evolutionary divergence of mammalian germlines.