PT  - JOURNAL ARTICLE
AU  - Dylan Kotliar
AU  - Adrian Veres
AU  - M. Aurel Nagy
AU  - Shervin Tabrizi
AU  - Eran Hodis
AU  - Douglas A. Melton
AU  - Pardis C. Sabeti
TI  - Identifying Gene Expression Programs of Cell-type Identity and Cellular Activity with Single-Cell RNA-Seq
AID  - 10.1101/310599
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 310599
4099  - http://biorxiv.org/content/early/2018/11/20/310599.short
4100  - http://biorxiv.org/content/early/2018/11/20/310599.full
AB  - Identifying gene expression programs underlying both cell-type identity and cellular activities (e.g. life-cycle processes, responses to environmental cues) is crucial for understanding the organization of cells and tissues. Although single-cell RNA-Seq (scRNA-Seq) can quantify transcripts in individual cells, each cell’s expression profile may be a mixture of both types of programs, making them difficult to disentangle. Here we illustrate and enhance the use of matrix factorization as a solution to this problem. We show with simulations that a method that we call consensus non-negative matrix factorization (cNMF) accurately infers identity and activity programs, including the relative contribution of programs in each cell. Applied to published brain organoid and visual cortex scRNA-Seq datasets, cNMF refines the hierarchy of cell types and identifies both expected (e.g. cell cycle and hypoxia) and intriguing novel activity programs. We propose that one of the novel programs may reflect a neurosecretory phenotype and a second may underlie the formation of neuronal synapses. We make cNMF available to the community and illustrate how this approach can provide key insights into gene expression variation within and between cell types.