MicroRNAs organize intrinsic variation into stem cell states

Area of Science:

• Developmental Biology
• Stem Cell Biology
• Gene Regulation

Background:

• Embryonic stem cells (ESCs) possess pluripotency, enabling differentiation into various adult cell types.
• Cellular diversity was traditionally attributed to external morphogen gradients.
• An alternative hypothesis suggests internal gene regulatory network fluctuations contribute to cell diversity.

Purpose of the Study:

• To investigate the role of intrinsic heterogeneity in ESCs in generating cell diversity.
• To explore the contribution of gene regulatory network fluctuations to cell state variation.
• To elucidate the function of microRNAs (miRNAs) in organizing cell state heterogeneity.

Main Methods:

• Analysis of gene expression states in ESCs.
• Investigation of microRNA activity and its targets.
• Experimental manipulation of miRNA function to assess effects on cell state transitions.

Main Results:

• ESCs exhibit intrinsic heterogeneity and interconverting cell states even without external gradients.
• Distinct developmental gene expression programs and miRNA activities characterize these cell states.
• MicroRNAs modulate pluripotency gene neighborhoods, increasing target gene and cell state variation.
• Loss of specific miRNAs hinders target variation and delays state transitions.

Conclusions:

• Gene regulatory networks can leverage intrinsic cellular variation to establish robust gene expression states.
• Variable miRNAs are crucial for organizing and propagating variation, facilitating state transitions.
• The interplay between intrinsic heterogeneity and environmental signals is vital for developmental outcomes.