Deconstructing transcriptional heterogeneity in pluripotent stem cells

Area of Science:

• Stem Cell Biology
• Molecular Biology
• Epigenetics

Background:

• Pluripotent stem cells (PSCs) can interconvert between states, but the regulatory mechanisms are unclear.
• Understanding transcriptional heterogeneity in PSCs is crucial for developmental biology and regenerative medicine.

Purpose of the Study:

• To characterize transcriptional heterogeneity in mouse PSCs using single-cell expression profiling.
• To investigate the influence of chemical and genetic perturbations on PSC states and transitions.

Main Methods:

• Single-cell expression profiling of mouse PSCs.
• Application of chemical and genetic perturbations, including microRNA manipulation and signaling pathway inhibition.
• Analysis of gene expression variability, population heterogeneity, and chromatin states.

Main Results:

• Signaling factors and developmental regulators exhibit significant expression variability in PSCs.
• Perturbations of signaling pathways and chromatin regulators impact expression variability and heterogeneity.
• Removal of microRNAs or blockage of signaling pathways induces a low-noise PSC ground state with a reconfigured pluripotency network and enhanced self-renewal.

Conclusions:

• Transcriptional heterogeneity is a key feature of PSCs, influenced by signaling and chromatin regulators.
• Specific microRNA families acting on the Myc/Lin28/let-7 axis mediate the transition to a stable PSC ground state.
• These findings offer insights into PSC state regulation and potential therapeutic applications.