ArticleProceedings of the National Academy of Sciences of the United States of America2014
p53 Suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 38 citations in OpenAlex.
- Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome.Nature communications · 2024Article
- Significant improvement of cardiac outflow tract septation defects in a DiGeorge syndrome model after minoxidil treatment.Biochemical and biophysical research communications · 2024Article
- An Updated Review on the Significance of DNA and Protein Methyltransferases and De-methylases in Human Diseases: From Molecular Mechanism to Novel Therapeutic Approaches.Current medicinal chemistry · 2024Review
- Understanding Heart Field Progenitor Cells for Modeling Congenital Heart Diseases.Current cardiology reports · 2021Review
- Pharmacological Rescue of the Brain Cortex Phenotype ofFrontiers in molecular neuroscience · 2021Article
- NCBP3/SNHG6 inhibits GBX2 transcription in a histone modification manner to facilitate the malignant biological behaviour of glioma cells.RNA biology · 2021Article
- Article
- Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes.American journal of medical genetics. Part C, Seminars in medical genetics · 2020Review
- Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner.Nature communications · 2019Article
- The role of p53 in developmental syndromes.Journal of molecular cell biology · 2019Review
- Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome.Human molecular genetics · 2016Article
- Rebalancing gene haploinsufficiency in vivo by targeting chromatin.Nature communications · 2016Article
- 22q11.2 deletion syndrome.Nature reviews. Disease primers · 2015Review
- Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome.Trends in genetics : TIG · 2015Review
- Whole-Genome Sequencing and Integrative Genomic Analysis Approach on Two 22q11.2 Deletion Syndrome Family Trios for Genotype to Phenotype Correlations.Human mutation · 2015Article
- MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus.Human molecular genetics · 2015Article
- Guilty as CHARGED: p53's expanding role in disease.Cell cycle (Georgetown, Tex.) · 2014Article
- Fgf8 promotes survival of nephron progenitors by regulating BAX/BAK-mediated apoptosis.Differentiation; research in biological diversityArticle
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
T-box 1 (Tbx1), a gene encoding a T-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene in humans causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we found a strong genetic interaction between Tbx1 and transformation related protein 53 (Trp53). Indeed, genetic ablation of Trp53, or pharmacological inhibition of its protein product p53, rescues significantly the cardiovascular defects of Tbx1 heterozygous and hypomorphic mutants. We found that the Tbx1 and p53 proteins do not interact directly but both occupy a genetic element of Gbx2, which is required for aortic arch and cardiac outflow tract development, and is a known genetic interactor of Tbx1. We found that Gbx2 expression is down-regulated in Tbx1(+/-) embryos and is restored to normal levels in Tbx1(+/-);Trp53(+/-) embryos. In addition, we found that the genetic element that binds both Tbx1 and p53 is highly enriched in H3K27 trimethylation, and upon p53 suppression H3K27me3 levels are reduced, along with Ezh2 enrichment. This finding suggests that the rescue of Gbx2 expression in Tbx1(+/-);Trp53(+/-) embryos is due to reduction of repressive chromatin marks. Overall our data identify unexpected genetic interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.