Identification of gene specific cis-regulatory elements during differentiation of mouse embryonic stem cells: An integrative approach using high-throughput datasets

PLoS Comput Biol. 2019 Nov 4;15(11):e1007337. doi: 10.1371/journal.pcbi.1007337. eCollection 2019 Nov.

Abstract

Gene expression governs cell fate, and is regulated via a complex interplay of transcription factors and molecules that change chromatin structure. Advances in sequencing-based assays have enabled investigation of these processes genome-wide, leading to large datasets that combine information on the dynamics of gene expression, transcription factor binding and chromatin structure as cells differentiate. While numerous studies focus on the effects of these features on broader gene regulation, less work has been done on the mechanisms of gene-specific transcriptional control. In this study, we have focussed on the latter by integrating gene expression data for the in vitro differentiation of murine ES cells to macrophages and cardiomyocytes, with dynamic data on chromatin structure, epigenetics and transcription factor binding. Combining a novel strategy to identify communities of related control elements with a penalized regression approach, we developed individual models to identify the potential control elements predictive of the expression of each gene. Our models were compared to an existing method and evaluated using the existing literature and new experimental data from embryonic stem cell differentiation reporter assays. Our method is able to identify transcriptional control elements in a gene specific manner that reflect known regulatory relationships and to generate useful hypotheses for further testing.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Differentiation / physiology
  • Chromatin / metabolism
  • Databases, Genetic
  • Epigenesis, Genetic
  • Epigenomics
  • Gene Expression Regulation / genetics
  • Genome
  • High-Throughput Screening Assays / methods*
  • Macrophages / metabolism
  • Mice
  • Mouse Embryonic Stem Cells / metabolism
  • Myocytes, Cardiac / metabolism
  • Promoter Regions, Genetic
  • Regulatory Elements, Transcriptional / genetics*
  • Regulatory Sequences, Nucleic Acid
  • Transcription Factors / metabolism

Substances

  • Chromatin
  • Transcription Factors