Hard-wired heterogeneity in blood stem cells revealed using a dynamic regulatory network model

Area of Science:

• Developmental Biology
• Systems Biology
• Genomics

Background:

• Transcription factor and cis-regulatory element interactions drive metazoan development.
• Haematopoiesis serves as a model for mammalian differentiation.
• Previous cis-regulatory network models were limited to pairwise interactions.

Purpose of the Study:

• To construct a Boolean network model of cis-regulatory interactions in haematopoietic stem/progenitor cells (HSPCs).
• To gain insights into cellular fate and differentiation through network modeling.
• To identify novel regulatory mechanisms controlling stem cell differentiation.

Main Methods:

• Generated a Boolean network model using cis-regulatory functional data for 11 HSPC regulator genes.
• Analyzed the model's state space using strongly connected components and shortest-path analysis.
• Experimentally validated model predictions, including a novel Gata1-Fli1 interaction.

Main Results:

• The model predicts heterogeneous expression patterns and intermediate states in HSPCs.
• An external trigger is necessary to exit the stem cell state, with distinct triggers for different lineages.
• A novel negative regulation of Fli1 by Gata1 was predicted and experimentally confirmed.

Conclusions:

• Advanced mammalian regulatory network models based on validated cis-regulatory interactions can yield novel hypotheses.
• This approach facilitates the study of transcriptional mechanisms controlling mammalian stem cell differentiation.
• The model provides a framework for understanding complex cellular state transitions.