Overactivation of tumour suppressor p53 has been associated with several bone marrow failure syndromes, such as dyskeratosis congenita, Fanconi anaemia and Diamond–Blackfan anaemia. Patients with certain bone marrow syndromes can present brain abnormalities, such as cerebellar hypoplasia, which has also been associated with increased p53 activity, along with microcephaly. The mechanism underlying p53 dysregulation in blood and brain abnormalities is not yet fully understood.
Toledo and colleagues aimed to determine whether p53 mediates transcriptional repression in these disorders indirectly via the DREAM (dimerization partner, RB-like, E2F4/E2F5 and MuvB) complex, which coordinates cell cycle-dependent gene repression. The authors used a Gene Ontology tool to analyse microarray data from murine bone marrow cells and cross-checked these data against homologous genes in the Human Phenotype Ontology website. The authors identified 499 genes downregulated upon p53 activation that are associated with haematopoiesis, several bone marrow syndromes and pathways involved in certain bone marrow syndromes, such as telomere biology, DNA repair pathways and ribosomal function. The authors then analysed data in the ChIP-Atlas to determine that 269 of the p53-downregulated genes were strongly bound by two subunits of the DREAM complex in mouse and/or human cells. Finally, the authors analysed publicly available RNA-sequencing data from murine haematopoietic stem cells and splenic cells with variant or knockdown p53 to confirm that 213 of these 269 genes were downregulated by p53. This approach was adapted to identify 162 genes associated with different brain abnormalities as targets of the p53-DREAM pathway, 58 of which had been implicated in abnormal haematopoiesis.
The authors then optimised positional frequency matrices to predict DREAM-binding sites (DBSs) within the promoter region of the 317 p53-DREAM target genes associated with blood and/or brain abnormalities. They found that 151 of these genes contained at least one DBS in their promoter region in the same orientation as transcription, near transcription start sites, and with a high level of conservation between mouse and human. Importantly, 106 of these genes are mutated in patients with a blood or brain genetic disorder.
Overall, Toledo and colleagues explored the core role of p53 in several blood and brain abnormalities, revealing several potentially pathological mechanisms that involve the DREAM pathway and highlighting parallels between the pathologies. Furthermore, the authors have developed robust resources and a workflow to enable the examination of the DREAM complex in a range of diseases.
The image shows bone marrow hypocellularity in a bone section from a p53Δ31/Δ31 mouse, a mouse model of dyskeratosis congenita. For permission to reuse, please contact Franck Toledo ([email protected]).
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