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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks
Martin Fischer1, Patrick Grossmann2, Megha Padi3
1Molecular Oncology, Medical School, University of Leipzig, Leipzig 04103, Germany Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA Department of Medicine, Harvard Medical School, Boston, MA 02215, USA Martin.Fischer@medizin.uni-leipzig.de Martin_Fischer@dfci.harvard.edu.
Abstract:
Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.
Insights
This study introduces a meta-analysis to identify reliable TP53 and cell cycle (CC) target genes, overcoming variations in previous research. It reveals key regulatory networks and provides a web tool for gene regulation assessment.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Cell cycle (CC) and TP53 regulatory networks are crucial in cancer, but individual studies show significant variations.
- Assessing gene regulation by TP53 and CC has been challenging due to inconsistencies across genome-wide studies.
Purpose of the Study:
- To develop a meta-analysis approach for identifying high-confidence TP53 and CC target genes.
- To generate gene regulatory networks by integrating differential expression and ChIP-seq data.
- To create a web-based atlas for assessing human gene regulation.
Main Methods:
- Meta-analysis of independent datasets to identify frequently reported target genes.
- Generation of gene regulatory networks by comparing gene expression with ChIP-seq data for TP53, RB1, E2F, DREAM, B-MYB, FOXM1, and MuvB.
- Analysis of RNA-seq data from p21-null cells to understand TP53-mediated gene downregulation.
Main Results:
- TP53-mediated gene downregulation typically requires p21 (CDKN1A).
- TP53-downregulated genes are also bound by the DREAM complex, indicating cell cycle regulation.
- Specific transcription factors (RB, E2F1, E2F7, B-MYB, FOXM1, MuvB) were mapped to distinct cell cycle phases (G1/S and G2/M).
Conclusions:
- The developed meta-analysis approach provides high-confidence, ranked target gene maps for key regulators.
- This method enables the prediction and differentiation of cell cycle regulation.
- A web atlas (www.targetgenereg.org) is available for exploring gene regulation.
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