Complex regulatory networks influence pluripotent cell state transitions in human iPSCs

Area of Science:

• Stem cell biology
• Epigenetics
• Genomics

Background:

• Human induced pluripotent stem cells (hiPSCs) exist in diverse, interconvertible pluripotent states in vitro.
• The proportions of these states vary significantly between different hiPSC lines.

Purpose of the Study:

• To investigate the gene and regulatory network modules underlying pluripotency in hiPSCs.
• To explore the role of genetic variants and epigenetic complexity in regulating hiPSC states.

Main Methods:

• Analysis of hundreds of hiPSC lines from diverse individuals.
• Identification of gene network modules (GNMs) and regulatory network modules (RNMs).
• Epigenetic and genetic analyses, including chromatin accessibility and regulatory variant identification.

Main Results:

• Discovered 13 highly correlated GNMs and 13 RNMs, suggesting coordinated gene expression and regulatory element accessibility.
• Revealed greater complexity in regulatory networks governing self-renewal and pluripotency than previously understood.
• Identified thousands of regulatory variants associated with chromatin accessibility, with significant enrichment in the NANOG-OCT4 Complex network.

Conclusions:

• Pluripotency and self-renewal involve intricate regulatory networks.
• Genetic factors, particularly variants affecting key regulators like the NANOG-OCT4 Complex, contribute to variations in pluripotent states within hiPSC lines.
• These findings suggest genetic contributions to cell state transitions in hiPSCs.