Time course regulatory analysis based on paired expression and chromatin accessibility data

Genome Res. 2020 Apr;30(4):622-634. doi: 10.1101/gr.257063.119. Epub 2020 Mar 18.

Abstract

A time course experiment is a widely used design in the study of cellular processes such as differentiation or response to stimuli. In this paper, we propose time course regulatory analysis (TimeReg) as a method for the analysis of gene regulatory networks based on paired gene expression and chromatin accessibility data from a time course. TimeReg can be used to prioritize regulatory elements, to extract core regulatory modules at each time point, to identify key regulators driving changes of the cellular state, and to causally connect the modules across different time points. We applied the method to analyze paired chromatin accessibility and gene expression data from a retinoic acid (RA)-induced mouse embryonic stem cells (mESCs) differentiation experiment. The analysis identified 57,048 novel regulatory elements regulating cerebellar development, synapse assembly, and hindbrain morphogenesis, which substantially extended our knowledge of cis-regulatory elements during differentiation. Using single-cell RNA-seq data, we showed that the core regulatory modules can reflect the properties of different subpopulations of cells. Finally, the driver regulators are shown to be important in clarifying the relations between modules across adjacent time points. As a second example, our method on Ascl1-induced direct reprogramming from fibroblast to neuron time course data identified Id1/2 as driver regulators of early stage of reprogramming.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Lineage
  • Cellular Reprogramming / genetics
  • Cellular Reprogramming Techniques
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • Computational Biology / methods
  • Gene Expression Profiling / methods
  • Gene Expression Regulation*
  • Gene Regulatory Networks
  • Mice
  • Mouse Embryonic Stem Cells / drug effects
  • Mouse Embryonic Stem Cells / metabolism*
  • Transcription Factors / metabolism
  • Transcriptome
  • Tretinoin / pharmacology

Substances

  • Chromatin
  • Transcription Factors
  • Tretinoin