Focus on the edges: a biomolecular network of histone PTMs, metabolites and proteins unveils functional entanglement in AML

The cell phenotype is not a direct manifestation of the genotype but rather a product of cellular history and the environmental context. However, individual biomolecules cannot change independently and show coordinated behavior. To study this in acute myeloid leukemia (AML), we built a unique multi-omics biomolecular network made from proteins, metabolites and histone posttranslational modifications (hPTMs) sequentially extracted from each cell pellet. Edges between the nodes are measured directly using 400 LC-MSMS runs that cover 18 AML cell lines. We provide a novel conceptual framework to illustrate the different classes of functional entanglement between and within omics layers and present the data in three interactive data browsers to allow full community access. To help navigate the network, we approach it from the perspective of two biomolecular targets, i.e. CD34 and the epigenetic mark Histone H3 lysine 27 trimethylation (H3K27me3). Now, this easily accessible biomolecular network serves as a starting point for building and testing hypotheses and streamlining drug development, in the process positioning biomolecular associations center stage in understanding phenotypic complexity.