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The epigenetic Oct4 gene regulatory network: stochastic analysis of different cellular reprogramming approaches
Simone Bruno1, Domitilla Del Vecchio1
1Department of Mechanical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139.
Biorxiv : the Preprint Server for Biology
|March 13, 2023
Summary
Overexpressing chromatin modifiers accelerates cellular reprogramming, making it faster and less variable. TET enzyme overexpression is more efficient than JMJD2 when DNA methylation binding is weak.
Area of Science:
- Cellular reprogramming
- Epigenetics
- Systems biology
Background:
- Chromatin modifications critically influence cellular reprogramming.
- Differentiated cells can be converted to a pluripotent state via reprogramming.
- Understanding reprogramming mechanisms is key for regenerative medicine.
Approach:
- Developed a gene regulatory network model incorporating chromatin modification effects.
- Simulated three reprogramming strategies: TF overexpression alone, with TET, or with JMJD2.
- Evaluated reprogramming speed (latency) and consistency (variability) computationally.
Key Points:
- Overexpressing chromatin "eraser" enzymes (TET or JMJD2) alongside transcription factors (Oct4) speeds up reprogramming.
- TET overexpression shows greater efficiency than JMJD2 under specific conditions (weak DNA methylation binding, low MBD protein).
- Computational model elucidates experimental findings and aids in optimizing reprogramming protocols.
Conclusions:
- Combining transcription factor overexpression with chromatin modifiers enhances reprogramming efficiency.
- The choice of chromatin modifier impacts reprogramming speed and efficiency.
- This model serves as a tool for designing improved cellular reprogramming strategies.
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