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Bradley E Bernstein1, Tarjei S Mikkelsen, Xiaohui Xie

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Highly conserved noncoding elements (HCNEs) in mammals are near developmental genes. Researchers found "bivalent domains" of histone methylation in embryonic stem cells, poised to activate these genes.

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Area of Science:

  • Genomics
  • Epigenetics
  • Developmental Biology

Background:

  • Highly conserved noncoding elements (HCNEs) are frequently located near genes critical for development.
  • These HCNE-rich regions are hypothesized to harbor essential regulatory elements controlling developmental processes.

Purpose of the Study:

  • To investigate the epigenetic landscape of HCNE-rich regions in mouse embryonic stem (ES) cells.
  • To identify specific histone modification patterns associated with these regulatory regions and their linked genes.

Main Methods:

  • Analysis of histone methylation patterns (H3K27me and H3K4me) across 56 large HCNE-rich loci in mouse ES cells.
  • Correlation of methylation patterns with the expression of nearby transcription factor (TF) genes.

Main Results:

  • Identification of "bivalent domains" characterized by H3K27 methylation encompassing H3K4 methylation in ES cells.
  • Bivalent domains were predominantly found at developmentally important transcription factor genes expressed at low levels.
  • A strong correlation between DNA sequence and histone methylation was observed in ES cells, diminishing upon differentiation.

Conclusions:

  • Bivalent domains may function to silence developmental genes in ES cells, maintaining them in a poised state for rapid activation.
  • DNA sequence plays a crucial role in establishing the initial epigenetic state of these regions.
  • A novel chromatin-based mechanism for maintaining pluripotency is suggested, involving the interplay of DNA sequence and epigenetic modifications.