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Updated: Jul 17, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
A systematic approach identifies p53-DREAM pathway target genes associated with blood or brain abnormalities
Jeanne Rakotopare1,2,3,4, Vincent Lejour1,2,3,4, Carla Duval1,2,3,4
1Genetics of Tumor Suppression, Institut Curie, Paris 75248 Cedex 05, France.
Abstract:
p53 (encoded by Trp53) is a tumor suppressor, but mouse models have revealed that increased p53 activity may cause bone marrow failure, likely through dimerization partner, RB-like, E2F4/E2F5 and MuvB (DREAM) complex-mediated gene repression. Here, we designed a systematic approach to identify p53-DREAM pathway targets, the repression of which might contribute to abnormal hematopoiesis. We used Gene Ontology analysis to study transcriptomic changes associated with bone marrow cell differentiation, then chromatin immunoprecipitation-sequencing (ChIP-seq) data to identify DREAM-bound promoters. We next created positional frequency matrices to identify evolutionary conserved sequence elements potentially bound by DREAM. The same approach was developed to find p53-DREAM targets associated with brain abnormalities, also observed in mice with increased p53 activity. Putative DREAM-binding sites were found for 151 candidate target genes, of which 106 are mutated in a blood or brain genetic disorder. Twenty-one DREAM-binding sites were tested and found to impact gene expression in luciferase assays, to notably regulate genes mutated in dyskeratosis congenita (Rtel1), Fanconi anemia (Fanca), Diamond-Blackfan anemia (Tsr2), primary microcephaly [Casc5 (or Knl1), Ncaph and Wdr62] and pontocerebellar hypoplasia (Toe1). These results provide clues on the role of the p53-DREAM pathway in regulating hematopoiesis and brain development, with implications for tumorigenesis.
Insights
Increased tumor suppressor p53 activity can cause bone marrow failure by repressing genes via the p53-DREAM complex. This study identifies key targets of this pathway, revealing its role in hematopoiesis and brain development.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- The tumor suppressor p53 (Trp53) plays a critical role in cellular regulation.
- However, excessive p53 activity in mouse models is linked to bone marrow failure, potentially via the DREAM complex.
- The DREAM complex mediates gene repression, impacting cellular processes.
Purpose of the Study:
- To systematically identify p53-DREAM pathway target genes.
- To understand how repression of these targets contributes to abnormal hematopoiesis and brain development.
- To investigate the role of the p53-DREAM pathway in genetic disorders.
Main Methods:
- Gene Ontology analysis of transcriptomic data from bone marrow cells.
- Chromatin immunoprecipitation-sequencing (ChIP-seq) to identify DREAM-bound promoters.
- Positional frequency matrices to detect conserved DREAM-binding elements.
- Luciferase assays to validate gene regulation by DREAM-binding sites.
Main Results:
- Identified 151 candidate p53-DREAM target genes, with 106 mutated in blood or brain disorders.
- Validated 21 DREAM-binding sites affecting gene expression.
- Demonstrated regulation of genes implicated in dyskeratosis congenita, Fanconi anemia, Diamond-Blackfan anemia, primary microcephaly, and pontocerebellar hypoplasia.
Conclusions:
- The p53-DREAM pathway is crucial for regulating hematopoiesis and brain development.
- Dysregulation of this pathway contributes to various genetic blood and brain disorders.
- Findings offer insights into the mechanisms underlying p53-related pathologies and tumorigenesis.
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