Novel 4D Tensor Decomposition-Based Approach Integrating Tri-Omics Profiling Data Can Identify Functionally Relevant Gene Clusters

Understanding gene expression requires integrating multiple regulatory layers, because transcript abundance does not necessarily correspond to translational activity or protein abundance. Ribosome profiling and proteomics help distinguish increased translation from ribosome stacking or translational buffering, but no de facto standard framework exists for unsupervised integration of transcriptome, translatome, and proteome profiles. Here, we propose a four-dimensional tensor decomposition-based unsupervised feature extraction approach for tri-omics integration. We applied higher-order singular value decomposition to transcriptome, Ribo-seq, and proteome profiles measured under branched-chain amino acid starvation. The resulting singular value vectors captured relationships among the three omics layers, including a component consistent with ribosome stacking, where transcriptome and translatome signals increased while proteome signals decreased, and another consistent with translational buffering, where proteome variation was suppressed despite transcriptome and translatome changes. Gene selection identified 1781 genes associated with ribosome stacking and 227 genes associated with translational buffering. Enrichment analyses linked the former to translation, post-translational protein modification, RNA polymerase II transcription, cell cycle regulation, endoplasmic reticulum protein processing, ubiquitin-mediated proteolysis, and stress-related pathways, and the latter to ribosome, translation elongation and termination, spliceosome, immune- and stress-related pathways, and ribosomopathy-associated diseases. Robustness analyses indicated that the results were not substantially affected by the duplicated proteome replicate or missing-value handling. Under the tested settings, comparison with MOFA+ and mixOmics suggested that our approach more directly extracted components interpretable as ribosome stacking and translational buffering. These results demonstrate that tensor decomposition-based unsupervised feature extraction is useful for identifying functionally relevant gene clusters from tri-omics data.