Nuclear gene proximity and protein interactions shape transcript covariations in mammalian single cells

Nat Commun. 2020 Oct 28;11(1):5445. doi: 10.1038/s41467-020-19011-5.


Single-cell RNA sequencing studies on gene co-expression patterns could yield important regulatory and functional insights, but have so far been limited by the confounding effects of differentiation and cell cycle. We apply a tailored experimental design that eliminates these confounders, and report thousands of intrinsically covarying gene pairs in mouse embryonic stem cells. These covariations form a network with biological properties, outlining known and novel gene interactions. We provide the first evidence that miRNAs naturally induce transcriptome-wide covariations and compare the relative importance of nuclear organization, transcriptional and post-transcriptional regulation in defining covariations. We find that nuclear organization has the greatest impact, and that genes encoding for physically interacting proteins specifically tend to covary, suggesting importance for protein complex formation. Our results lend support to the concept of post-transcriptional RNA operons, but we further present evidence that nuclear proximity of genes may provide substantial functional regulation in mammalian single cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Gene Regulatory Networks*
  • Genetic Variation
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism
  • Protein Interaction Maps*
  • RNA-Seq
  • Ribonuclease III / deficiency
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • Single-Cell Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome


  • MicroRNAs
  • Transcription Factors
  • Drosha protein, mouse
  • Ribonuclease III