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Ultraconserved Enhancers Are Required for Normal Development.

Diane E Dickel1, Athena R Ypsilanti2, Ramón Pla2

  • 1Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA.

Cell
|January 24, 2018
PubMed
Summary
This summary is machine-generated.

Ultraconserved enhancers are crucial for normal mammalian development. Deleting these sequences near the Arx gene in mice caused subtle neurological and growth defects, revealing their hidden importance.

Keywords:
Arxbrain developmentenhancergene regulationhippocampusin vivoknockoutneuronsnoncodingultraconserved

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Area of Science:

  • Genomics
  • Developmental Biology
  • Neuroscience

Background:

  • Non-coding ultraconserved regions (UCRs) are highly conserved sequences across mammalian genomes.
  • These UCRs can act as distant-acting enhancers, regulating gene expression.
  • Previous studies showed no immediate impact of UCR deletion on viability.

Purpose of the Study:

  • To investigate the role of ultraconserved enhancers in normal development.
  • To determine the functional importance of specific UCRs located near the Arx gene.

Main Methods:

  • Utilized genome editing to create knockout mice lacking individual or combinations of UCRs.
  • Focused on the longest UCRs genome-wide, particularly those near the Arx gene.
  • Analyzed neurological and growth phenotypes in mutant mice.

Main Results:

  • Mice with single or pairwise UCR deletions were viable and fertile.
  • Nearly all mutant mice exhibited neurological abnormalities and growth defects.
  • Observed substantial alterations in neuron populations and structural brain defects.

Conclusions:

  • Ultraconserved enhancers are essential for normal mammalian development.
  • Strong sequence conservation in UCRs likely reflects fitness deficits not apparent in standard laboratory conditions.
  • These findings highlight the functional significance of UCRs in development and evolution.