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Cell. 2018 Jan 25;172(3):491-499.e15. doi: 10.1016/j.cell.2017.12.017. Epub 2018 Jan 18.

Ultraconserved Enhancers Are Required for Normal Development.

Author information

1
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA. Electronic address: dedickel@lbl.gov.
2
Department of Psychiatry, Neuroscience Program, UCSF Weill Institute for Neurosciences and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA 94158, USA.
3
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA.
4
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; Comparative Biochemistry Program, University of California Berkeley, Berkeley, CA 94720, USA. Electronic address: lapennacchio@lbl.gov.
5
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California Merced, Merced, CA 95343, USA. Electronic address: avisel@lbl.gov.

Abstract

Non-coding "ultraconserved" regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers. Mice with single or pairwise deletions of ultraconserved enhancers were viable and fertile but in nearly all cases showed neurological or growth abnormalities, including substantial alterations of neuron populations and structural brain defects. Our results demonstrate the functional importance of ultraconserved enhancers and indicate that remarkably strong sequence conservation likely results from fitness deficits that appear subtle in a laboratory setting.

KEYWORDS:

Arx; brain development; enhancer; gene regulation; hippocampus; in vivo; knockout; neurons; noncoding; ultraconserved

PMID:
29358049
PMCID:
PMC5786478
[Available on 2019-01-25]
DOI:
10.1016/j.cell.2017.12.017
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