Single‐Cell Simultaneous Metabolome and Transcriptome Profiling Revealing Metabolite‐Gene Correlation Network

Abstract Metabolic studies at the single cell level can directly define the cellular phenotype closest to physiological or disease states. However, the current single cell metabolome (SCM) study using mass spectroscopy has difficulty giving a complete view of the metabolic activity in the cell, and the prediction of the metabolism‐phenotype relationship is limited by the potential inconsistency between transcriptomic and metabolic levels. Here, the single‐cell simultaneous metabolome and transcriptome profiling method (scMeT‐seq) is developed at one single cell, based on sub‐picoliter sampling from the cell for the initial metabolome profiling followed by single cell transcriptome sequencing. This design not only provides sufficient cytoplasm for SCM but also nicely keeps the cellular viability for the accurate transcriptomic analysis in the same cell. Integrative analysis of scMeT‐seq reveals both dynamical and cell state‐specific associations between metabolome and transcriptome in the macrophages with defined metabolic perturbations. Moreover, metabolite signatures are mapped to the single‐cell trajectory and gene correlation network of macrophage transition, which allows the unsupervised functional interpretation of metabolome. Thus, the established scMeT‐seq should lead to a new perspective in metabolic research by transforming metabolomics from a metabolite snapshot to a functional approach.