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Title: Ultraconserved Enhancers Are Required for Normal Development

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. 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.

Authors:
 [1];  [2];  [2];  [1];  [1];  [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3] more »;  [4] « less
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Environmental Genomics and Systems Biology Division
  2. Univ. of California, San Francisco, CA (United States). Dept. of Psychiatry. Neuroscience Program. UCSF Weill Inst. for Neurosciences. Nina Ireland Lab. of Developmental Neurobiology
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Environmental Genomics and Systems Biology Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Berkeley, CA (United States). Comparative Biochemistry Program
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Environmental Genomics and Systems Biology Division; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Merced, CA (United States). School of Natural Sciences
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Berkeley, CA (United States); Univ. of California, San Francisco, CA (United States)
Sponsoring Org.:
USDOE; LBNL Laboratory Directed Research and Development (LDRD) Program; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1548828
Alternate Identifier(s):
OSTI ID: 1506293
Grant/Contract Number:  
AC02-05CH11231; S10RR029668; S10RR027303; R01HG003988; R24HL123879; UM1HL098166; R01NS34661; R37MH049428
Resource Type:
Published Article
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 172; Journal Issue: 3; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; enhancer; ultraconserved; gene regulation; brain development; Arx; noncoding; knockout; in vivo; hippocampus; neurons

Citation Formats

Dickel, Diane E., Ypsilanti, Athena R., Pla, Ramón, Zhu, Yiwen, Barozzi, Iros, Mannion, Brandon J., Khin, Yupar S., Fukuda-Yuzawa, Yoko, Plajzer-Frick, Ingrid, Pickle, Catherine S., Lee, Elizabeth A., Harrington, Anne N., Pham, Quan T., Garvin, Tyler H., Kato, Momoe, Osterwalder, Marco, Akiyama, Jennifer A., Afzal, Veena, Rubenstein, John L. R., Pennacchio, Len A., and Visel, Axel. Ultraconserved Enhancers Are Required for Normal Development. United States: N. p., 2018. Web. doi:10.1016/j.cell.2017.12.017.
Dickel, Diane E., Ypsilanti, Athena R., Pla, Ramón, Zhu, Yiwen, Barozzi, Iros, Mannion, Brandon J., Khin, Yupar S., Fukuda-Yuzawa, Yoko, Plajzer-Frick, Ingrid, Pickle, Catherine S., Lee, Elizabeth A., Harrington, Anne N., Pham, Quan T., Garvin, Tyler H., Kato, Momoe, Osterwalder, Marco, Akiyama, Jennifer A., Afzal, Veena, Rubenstein, John L. R., Pennacchio, Len A., & Visel, Axel. Ultraconserved Enhancers Are Required for Normal Development. United States. doi:10.1016/j.cell.2017.12.017.
Dickel, Diane E., Ypsilanti, Athena R., Pla, Ramón, Zhu, Yiwen, Barozzi, Iros, Mannion, Brandon J., Khin, Yupar S., Fukuda-Yuzawa, Yoko, Plajzer-Frick, Ingrid, Pickle, Catherine S., Lee, Elizabeth A., Harrington, Anne N., Pham, Quan T., Garvin, Tyler H., Kato, Momoe, Osterwalder, Marco, Akiyama, Jennifer A., Afzal, Veena, Rubenstein, John L. R., Pennacchio, Len A., and Visel, Axel. Thu . "Ultraconserved Enhancers Are Required for Normal Development". United States. doi:10.1016/j.cell.2017.12.017.
@article{osti_1548828,
title = {Ultraconserved Enhancers Are Required for Normal Development},
author = {Dickel, Diane E. and Ypsilanti, Athena R. and Pla, Ramón and Zhu, Yiwen and Barozzi, Iros and Mannion, Brandon J. and Khin, Yupar S. and Fukuda-Yuzawa, Yoko and Plajzer-Frick, Ingrid and Pickle, Catherine S. and Lee, Elizabeth A. and Harrington, Anne N. and Pham, Quan T. and Garvin, Tyler H. and Kato, Momoe and Osterwalder, Marco and Akiyama, Jennifer A. and Afzal, Veena and Rubenstein, John L. R. and Pennacchio, Len A. and Visel, Axel},
abstractNote = {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. 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.},
doi = {10.1016/j.cell.2017.12.017},
journal = {Cell},
number = 3,
volume = 172,
place = {United States},
year = {2018},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1016/j.cell.2017.12.017

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Cited by: 26 works
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