Ultraconserved Enhancers Are Required for Normal Development

被引：136

作者：

Dickel, Diane E. ^{[1
]}

Ypsilanti, Athena R. ^{[2
,3
]}

Pla, Ramon ^{[2
,3
]}

Zhu, Yiwen ^{[1
]}

Barozzi, Iros ^{[1
]}

Mannion, Brandon J. ^{[1
]}

Khin, Yupar S. ^{[2
,3
]}

Fukuda-Yuzawa, Yoko ^{[1
]}

Plajzer-Frick, Ingrid ^{[1
]}

Pickle, Catherine S. ^{[1
]}

Lee, Elizabeth A. ^{[1
]}

Harrington, Anne N. ^{[1
]}

Pham, Quan T. ^{[1
]}

Garvin, Tyler H. ^{[1
]}

Kato, Momoe ^{[1
]}

Osterwalder, Marco ^{[1
]}

Akiyama, Jennifer A. ^{[1
]}

Afzal, Veena ^{[1
]}

Rubenstein, John L. R. ^{[2
,3
]}

Pennacchio, Len A. ^{[1
,4
,5
]}

Visel, Axel ^{[1
,4
,6
]}

机构：

[1] Lawrence Berkeley Natl Lab, Environm Genom & Syst Biol Div, 1 Cyclotron Rd, Berkeley, CA 94720 USA

[2] Univ Calif San Francisco, UCSF Weill Inst Neurosci, Neurosci Program, Dept Psychiat, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Nina Ireland Lab Dev Neurobiol, San Francisco, CA 94158 USA

[4] US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA

[5] Univ Calif Berkeley, Comparat Biochem Program, Berkeley, CA 94720 USA

[6] Univ Calif Merced, Sch Nat Sci, Merced, CA 95343 USA

来源：

CELL | 2018年 / 172卷 / 03期

基金：

瑞士国家科学基金会;

关键词：

ONE-STEP GENERATION; RNA-SEQ DATA; HUMAN GENOME; ARX; GENE; MICE; EXPRESSION; DIFFERENTIATION; TELENCEPHALON; INTERNEURONS;

D O I：

10.1016/j.cell.2017.12.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 pair-wise 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.

引用

页码：491 / +

页数：24

共 49 条

[1] HEAVY-METAL INTENSIFICATION OF DAB-BASED HRP REACTION-PRODUCT [J].