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Functional cis-regulatory modules encoded by mouse-specific endogenous retrovirus.

Vasavi Sundaram1,2, Mayank N K Choudhary1,2, Erica Pehrsson2

  • 1Division of Biological and Biomedical Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, Missouri 63110, USA.

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Mouse-specific transposable elements (TEs) contain regulatory modules that enhance gene expression in embryonic stem cells (ESCs). These findings suggest ancient TE insertions may have introduced cis-regulatory modules into the mouse genome.

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Area of Science:

  • Genomics
  • Molecular Biology
  • Developmental Biology

Background:

  • Cis-regulatory modules control gene expression by integrating transcription factor (TF) binding.
  • Transposable elements (TEs) can distribute regulatory sequences throughout the genome, potentially acting as cis-regulatory modules.
  • The role of TEs in providing novel regulatory elements in mammalian genomes is an active area of research.

Purpose of the Study:

  • To investigate the presence and function of cis-regulatory modules within mouse-specific transposable elements (TEs).
  • To determine if these TE-derived modules can enhance gene expression in mouse embryonic stem cells (ESCs).
  • To explore the evolutionary origins of these regulatory modules by examining ancestral TE sequences.

Main Methods:

  • Identification and characterization of mouse-specific TEs.
  • Assays for enhancer activity of individual TEs in mouse ESCs.
  • Site-directed mutagenesis of TF-binding motifs within TEs.
  • In silico reconstruction and analysis of ancestral TEs.

Main Results:

  • The majority (77%) of tested mouse-specific TEs demonstrated enhancer activity in mouse ESCs.
  • A specific module of TF-binding motifs within TEs was found to cooperatively enhance gene expression.
  • The same cooperative motif module was identified in in silico constructed ancestral TEs, indicating conserved function.

Conclusions:

  • Mouse-specific TEs harbor functional cis-regulatory modules that enhance gene expression in ESCs.
  • These modules, composed of TF-binding motifs, act cooperatively to regulate gene activity.
  • Evidence suggests that ancestral TE insertions may have contributed cis-regulatory modules to the mouse genome, influencing gene regulation evolutionarily.