Inference of differentiation time for single cell transcriptomes using cell population reference data

Nat Commun. 2017 Nov 30;8(1):1856. doi: 10.1038/s41467-017-01860-2.

Abstract

Single-cell RNA sequencing (scRNA-seq) is a powerful method for dissecting intercellular heterogeneity during development. Conventional trajectory analysis provides only a pseudotime of development, and often discards cell-cycle events as confounding factors. Here using matched cell population RNA-seq (cpRNA-seq) as a reference, we developed an "iCpSc" package for integrative analysis of cpRNA-seq and scRNA-seq data. By generating a computational model for reference "biological differentiation time" using cell population data and applying it to single-cell data, we unbiasedly associated cell-cycle checkpoints to the internal molecular timer of single cells. Through inferring a network flow from cpRNA-seq to scRNA-seq data, we predicted a role of M phase in controlling the speed of neural differentiation of mouse embryonic stem cells, and validated it through gene knockout (KO) experiments. By linking temporally matched cpRNA-seq and scRNA-seq data, our approach provides an effective and unbiased approach for identifying developmental trajectory and timing-related regulatory events.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Cell Cycle / genetics
  • Cell Differentiation
  • Cell Division / genetics
  • Computational Biology / methods
  • Gene Regulatory Networks
  • High-Throughput Nucleotide Sequencing / methods
  • Mice
  • Mice, Knockout
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / physiology*
  • Proto-Oncogene Proteins c-fyn / genetics
  • Sequence Analysis, RNA / methods
  • Single-Cell Analysis / methods*
  • Smad1 Protein / genetics
  • Transcriptome*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Smad1 Protein
  • Smad1 protein, mouse
  • Tumor Suppressor Protein p53
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn