Journal Article

The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells

Morse, Michael, Li, Shuqiang, Cacchiarelli, Davide, Grimsby, Jonna, Mikkelsen, Tarjei S, Pokharel, Prapti, Lennon, Niall J, Livak, Kenneth J, Rinn, John L, Trapnell, Cole

2014

Overview

An algorithm uncovers transcriptome dynamics during differentiation by ordering RNA-Seq data from single cells. Defining the transcriptional dynamics of a temporal process such as cell differentiation is challenging owing to the high variability in gene expression between individual cells. Time-series gene expression analyses of bulk cells have difficulty distinguishing early and late phases of a transcriptional cascade or identifying rare subpopulations of cells, and single-cell proteomic methods rely on a priori knowledge of key distinguishing markers 1 . Here we describe Monocle, an unsupervised algorithm that increases the temporal resolution of transcriptome dynamics using single-cell RNA-Seq data collected at multiple time points. Applied to the differentiation of primary human myoblasts, Monocle revealed switch-like changes in expression of key regulatory factors, sequential waves of gene regulation, and expression of regulators that were not known to act in differentiation. We validated some of these predicted regulators in a loss-of function screen. Monocle can in principle be used to recover single-cell gene expression kinetics from a wide array of cellular processes, including differentiation, proliferation and oncogenic transformation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/62 / 45/91 / 631/114/2785 / 631/136/142 / 631/80 / Agriculture / Algorithms / Bioinformatics / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Cell differentiation / Cell Differentiation - genetics / Cell Differentiation - physiology / Cells / Cells, Cultured / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation - genetics / Gene Expression Regulation - physiology / Genetic aspects / Genetic regulation / Genomics / Humans / Kinetics / letter / Life Sciences / Methods / Muscle Development - genetics / Muscle Development - physiology / Myoblasts - metabolism / Reproducibility of Results / Subpopulations / Time series / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptome - genetics / Transcriptome - physiology