MicroRNAs organize intrinsic variation into stem cell states

Meenakshi Chakraborty, Sofia Hu, Erica Visness, Marco Del Giudice, Andrea De Martino, Carla Bosia, Phillip A Sharp, Salil Garg

Research output: Contribution to journalArticlepeer-review

Abstract

Pluripotent embryonic stem cells (ESCs) contain the potential to form a diverse array of cells with distinct gene expression states, namely the cells of the adult vertebrate. Classically, diversity has been attributed to cells sensing their position with respect to external morphogen gradients. However, an alternative is that diversity arises in part from cooption of fluctuations in the gene regulatory network. Here we find ESCs exhibit intrinsic heterogeneity in the absence of external gradients by forming interconverting cell states. States vary in developmental gene expression programs and display distinct activity of microRNAs (miRNAs). Notably, miRNAs act on neighborhoods of pluripotency genes to increase variation of target genes and cell states. Loss of miRNAs that vary across states reduces target variation and delays state transitions, suggesting variable miRNAs organize and propagate variation to promote state transitions. Together these findings provide insight into how a gene regulatory network can coopt variation intrinsic to cell systems to form robust gene expression states. Interactions between intrinsic heterogeneity and environmental signals may help achieve developmental outcomes.

Original languageEnglish
Pages (from-to)6942-6950
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number12
DOIs
Publication statusPublished - Mar 24 2020

Keywords

  • Animals
  • Argonaute Proteins/physiology
  • Cell Differentiation
  • Embryonic Stem Cells/cytology
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Mice
  • Mice, Knockout
  • MicroRNAs/genetics
  • Nanog Homeobox Protein/physiology
  • RNA-Binding Proteins/physiology
  • SOXB1 Transcription Factors/physiology
  • Signal Transduction

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