Inappropriate p53 activation during development induces features of CHARGE syndrome

Jeanine L. Van Nostrand, Colleen A. Brady, Heiyoun Jung, Daniel R. Fuentes, Margaret M. Kozak, Thomas M. Johnson, Chieh Yu Lin, Chien Jung Lin, Donald L. Swiderski, Hannes Vogel, Jonathan A. Bernstein, Tania Attié-Bitach, Ching-Pin Chang, Joanna Wysocka, Donna M. Martin, Laura D. Attardi

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53<sup>25,26,53,54</sup>), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53<sup>25,26,53,54</sup> mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53<sup>25,26,53,54/-</sup> embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

Original languageEnglish
Pages (from-to)228-232
Number of pages5
JournalNature
Volume514
Issue number7521
DOIs
StatePublished - Oct 9 2014

Fingerprint

CHARGE Syndrome
Phenotype
Coloboma
Embryonic Structures
Mutant Strains Mice
Alleles
Choanal Atresia
External Ear
Tumor Suppressor Protein p53
Congenital Heart Defects
Neural Crest
Inner Ear
Mutant Proteins
Cell Cycle Checkpoints
Growth and Development
Genes
Chromatin
Ear
Adenosine Triphosphate
Apoptosis

ASJC Scopus subject areas

  • General

Cite this

Van Nostrand, J. L., Brady, C. A., Jung, H., Fuentes, D. R., Kozak, M. M., Johnson, T. M., ... Attardi, L. D. (2014). Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature, 514(7521), 228-232. https://doi.org/10.1038/nature13585

Inappropriate p53 activation during development induces features of CHARGE syndrome. / Van Nostrand, Jeanine L.; Brady, Colleen A.; Jung, Heiyoun; Fuentes, Daniel R.; Kozak, Margaret M.; Johnson, Thomas M.; Lin, Chieh Yu; Lin, Chien Jung; Swiderski, Donald L.; Vogel, Hannes; Bernstein, Jonathan A.; Attié-Bitach, Tania; Chang, Ching-Pin; Wysocka, Joanna; Martin, Donna M.; Attardi, Laura D.

In: Nature, Vol. 514, No. 7521, 09.10.2014, p. 228-232.

Research output: Contribution to journalArticle

Van Nostrand, JL, Brady, CA, Jung, H, Fuentes, DR, Kozak, MM, Johnson, TM, Lin, CY, Lin, CJ, Swiderski, DL, Vogel, H, Bernstein, JA, Attié-Bitach, T, Chang, C-P, Wysocka, J, Martin, DM & Attardi, LD 2014, 'Inappropriate p53 activation during development induces features of CHARGE syndrome', Nature, vol. 514, no. 7521, pp. 228-232. https://doi.org/10.1038/nature13585
Van Nostrand JL, Brady CA, Jung H, Fuentes DR, Kozak MM, Johnson TM et al. Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature. 2014 Oct 9;514(7521):228-232. https://doi.org/10.1038/nature13585
Van Nostrand, Jeanine L. ; Brady, Colleen A. ; Jung, Heiyoun ; Fuentes, Daniel R. ; Kozak, Margaret M. ; Johnson, Thomas M. ; Lin, Chieh Yu ; Lin, Chien Jung ; Swiderski, Donald L. ; Vogel, Hannes ; Bernstein, Jonathan A. ; Attié-Bitach, Tania ; Chang, Ching-Pin ; Wysocka, Joanna ; Martin, Donna M. ; Attardi, Laura D. / Inappropriate p53 activation during development induces features of CHARGE syndrome. In: Nature. 2014 ; Vol. 514, No. 7521. pp. 228-232.
@article{0011e377e6634648a50739f1ac53716c,
title = "Inappropriate p53 activation during development induces features of CHARGE syndrome",
abstract = "CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90{\%} of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p5325,26,53,54), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p5325,26,53,54 mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p5325,26,53,54/- embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.",
author = "{Van Nostrand}, {Jeanine L.} and Brady, {Colleen A.} and Heiyoun Jung and Fuentes, {Daniel R.} and Kozak, {Margaret M.} and Johnson, {Thomas M.} and Lin, {Chieh Yu} and Lin, {Chien Jung} and Swiderski, {Donald L.} and Hannes Vogel and Bernstein, {Jonathan A.} and Tania Atti{\'e}-Bitach and Ching-Pin Chang and Joanna Wysocka and Martin, {Donna M.} and Attardi, {Laura D.}",
year = "2014",
month = "10",
day = "9",
doi = "10.1038/nature13585",
language = "English",
volume = "514",
pages = "228--232",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7521",

}

TY - JOUR

T1 - Inappropriate p53 activation during development induces features of CHARGE syndrome

AU - Van Nostrand, Jeanine L.

AU - Brady, Colleen A.

AU - Jung, Heiyoun

AU - Fuentes, Daniel R.

AU - Kozak, Margaret M.

AU - Johnson, Thomas M.

AU - Lin, Chieh Yu

AU - Lin, Chien Jung

AU - Swiderski, Donald L.

AU - Vogel, Hannes

AU - Bernstein, Jonathan A.

AU - Attié-Bitach, Tania

AU - Chang, Ching-Pin

AU - Wysocka, Joanna

AU - Martin, Donna M.

AU - Attardi, Laura D.

PY - 2014/10/9

Y1 - 2014/10/9

N2 - CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p5325,26,53,54), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p5325,26,53,54 mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p5325,26,53,54/- embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

AB - CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p5325,26,53,54), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p5325,26,53,54 mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p5325,26,53,54/- embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

UR - http://www.scopus.com/inward/record.url?scp=84908338814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908338814&partnerID=8YFLogxK

U2 - 10.1038/nature13585

DO - 10.1038/nature13585

M3 - Article

C2 - 25119037

AN - SCOPUS:84908338814

VL - 514

SP - 228

EP - 232

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7521

ER -