SUMMARY¶
Preprint: bioRxiv
SiRCle (Signature Regulatory Clustering) model integration reveals mechanisms of phenotype regulation in renal cancer¶
Ariane Mora^1, Christina Schmidt^2,3, Brad Balderson1, Christian Frezza3#, Mikael Bodén1#
School of Chemistry and Molecular Biosciences, University of Queensland, Molecular Biosciences Building 76, St Lucia QLD 4072, Australia.
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0X2, United Kingdom
CECAD Research Center, University Hospital Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
^Joint first authors #Joint last authors
Note Christina and Ariane are equal joint first authors and the authors may swap the order of their names as they so choose :)
Abstract¶
Clear cell renal cell carcinoma (ccRCC) tumours develop and progress via complex remodelling of the kidney epigenome, transcriptome, proteome, and metabolome. Given the subsequent tumour and inter-patient heterogeneity, drug-based treatments report limited success, calling for multi-omics studies to extract regulatory relationships, and ultimately, to develop targeted therapies. However, current methods are unable to extract nonlinear multi-omics perturbations.
Here, we present SiRCle (Signature Regulatory Clustering), a novel method to integrate DNA methylation, RNA-seq and proteomics data. Applying SiRCle to a case study of ccRCC, we disentangle the layer (DNA methylation, transcription and/or translation) where dysregulation first occurs and find the primary biological processes altered. Next, we detect regulatory differences between patient subsets by using a variational autoencoder to integrate omics’ data followed by statistical comparisons on the integrated space. In ccRCC patients, SiRCle allows to identify metabolic enzymes and cell-type-specific markers associated with survival along with the likely molecular driver behind the gene’s perturbations.
The general table of how we define regulatory clusters.
"""
| Methylation | RNAseq | Proteomics | Regulation driver_1 | Regulation driver_2 | Regulation_Grouping1 | Regulation_Grouping2 | Regulation_Grouping3 |
|------------------|-----------|------------|------------------------------|-------------------------|----------------------|----------------------|----------------------|
| Hypermethylation | DOWN | DOWN | Methylation increase (MDS) | None | MDS | MDS | MDS |
| Hypermethylation | UP | DOWN | mRNA increase (TPDE) | Protein decrease (TMDS) | TPDE+TMDS | TPDE+TMDS | TMDS |
| Hypermethylation | UP | UP | mRNA increase (TPDE) | None | TPDE | TPDE | TPDE |
| Hypermethylation | DOWN | UP | Methylation increase (MDS) | Protein increase (TMDE) | MDS+TMDE | TMDE | TMDE |
| Hypermethylation | No Change | UP | mRNA increase (TPDE) | Protein increase (TMDE) | TPDE+TMDE | TMDE | TMDE |
| Hypermethylation | No Change | DOWN | mRNA increase (TPDE) | Protein decrease (TMDS) | TPDE+TMDS | TMDS | TMDS |
| Hypermethylation | UP | No Change | mRNA increase (TPDE) | Protein decrease (TMDS) | TPDE+TMDS | TPDE+TMDS | TMDS |
| Hypermethylation | DOWN | No Change | Methylation increase (MDS) | Protein increase (TMDE) | MDS+TMDE | MDS+TMDE | TMDE |
| Hypermethylation | No Change | No Change | Methylation increase (ncRNA) | None | MDS-ncRNA | MDS_ncRNA | MDS_ncRNA |
| Hypomethylation | DOWN | DOWN | mRNA decrease (TPDS) | None | TPDS | TPDS | TPDS |
| Hypomethylation | UP | DOWN | Methylation decrease (MDE) | Protein decrease (TMDS) | MDE+TMDS | TMDS | TMDS |
| Hypomethylation | UP | UP | Methylation decrease (MDE) | None | MDE | MDE | MDE |
| Hypomethylation | DOWN | UP | mRNA decrease (TPDS) | Protein increase (TMDE) | TPDS+TMDE | TPDS+TMDE | TMDE |
| Hypomethylation | No Change | UP | mRNA decrease (TPDS) | Protein increase (TMDE) | TPDS+TMDE | TMDE | TMDE |
| Hypomethylation | No Change | DOWN | mRNA decrease (TPDS) | Protein decrease (TMDS) | TPDS+TMDS | TMDS | TMDS |
| Hypomethylation | UP | No Change | Methylation decrease (MDE) | Protein decrease (TMDS) | MDE+TMDS | MDE+TMDS | TMDS |
| Hypomethylation | DOWN | No Change | mRNA decrease (TPDS) | Protein increase (TMDE) | TPDS+TMDE | TPDS+TMDE | TMDE |
| Hypomethylation | No Change | No Change | Methylation decrease (ncRNA) | None | MDE+ncRNA | MDE_ncRNA | MDE_ncRNA |
| No Change | DOWN | UP | mRNA decrease (TPDS) | Protein increase (TMDE) | TPDS+TMDE | TPDS+TMDE | TMDE |
| No Change | UP | DOWN | mRNA increase (TPDE) | Protein decrease (TMDS) | TPDE+TMDS | TPDE+TMDS | TMDS |
| No Change | DOWN | DOWN | mRNA decrease (TPDS) | None | TPDS | TPDS | TPDS |
| No Change | UP | UP | mRNA increase (TPDE) | None | TPDE | TPDE | TPDE |
| No Change | No Change | UP | Protein increase (TMDE) | None | TMDE | TMDE | TMDE |
| No Change | No Change | DOWN | Protein decrease (TMDS) | None | TMDS | TMDS | TMDS |
| No Change | UP | No Change | mRNA increase (TPDE) | Protein decrease (TMDS) | TPDE+TMDS | TPDE+TMDS | TMDS |
| No Change | DOWN | No Change | mRNA decrease (TPDS) | Protein increase (TMDE) | TPDS+TMDE | TPDS+TMDE | TMDE |
| No Change | No Change | No Change | NoChange | NoChange | NoChange | NoChange | NoChange |
"""
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