MicroRNAs organize intrinsic variation into stem cell states

Proceedings of the National Academy of Sciences of the United States of America
Meenakshi ChakrabortySalil Garg

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.

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Citations

Sep 4, 2020·International Journal of Molecular Sciences·Giuseppina DivisatoSilvia Parisi
Feb 24, 2021·Cellular & Molecular Biology Letters·Yu LiuLiangcheng Zheng
Aug 18, 2021·IScience·Tee UdomlumleartSalil Garg

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Datasets Mentioned

BETA
GSE132708

Methods Mentioned

BETA
fluorescence microscopy
scRNA-seq
RNA-seq
immunoprecipitation
transfection
gene neighborhood
Fluorescence Activated Cell Sorting
PCR
electrophoresis

Software Mentioned

FACSDiva
GraphPad Prism
Python
plot
Zenodo
SeqWell
scipy
matplotlib
Agilent BioAnalyzer
ly

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