Epigenetic control of metabolic identity across cell types

Constraint-based network modelling is a powerful tool for analysing cellular metabolism at genomic scale. Here, we conducted an integrative analysis of metabolic networks reconstructed from RNA-seq data with paired epigenomic data from the EpiATLAS resource of the International Human Epigenome Consortium (IHEC). Applying a state-of-the-art contextualisation algorithm, we reconstructed metabolic networks across 1,555 samples corresponding to 58 tissues and cell types. Analysis of these networks revealed the distribution of metabolic functionalities across human cell types and provides a compendium of human metabolic activity. This integrative approach allowed us to define, across tissues and cell types, i) reactions that fulfil the basic metabolic processes (core metabolism), and ii) cell type-specific functions (unique metabolism), that shape the metabolic identity of a cell or a tissue. Integration with EpiATLAS-derived cell type-specific gene-level chromatin states and enhancer-gene interactions identified enhancers, transcription factors, and key nodes controlling core and unique metabolism. Transport and first reactions of pathways were enriched for high expression, active chromatin state, and Polycomb-mediated repression in cell types where pathways are inactive, suggesting that key nodes are targets of repression. This integrative analysis forms the basis for identifying regulation points that control metabolic identity in human cells.