Engineering Inducible Cell Fate Transitions by Harnessing Epigenetic Silencing.

Area of Science:

• Synthetic biology
• Epigenetics
• Cellular engineering

Background:

• Cell-cell communication drives cell fate transitions during development.
• Epigenetic gene regulation maintains these cell fate decisions.
• Engineering stable cell fate changes requires precise control over gene expression.

Purpose of the Study:

• To develop synthetic circuits that leverage endogenous epigenetic machinery for stable gene expression changes.
• To create input-controlled epigenetic switches for inducing self-sustaining silencing or activation of target genes.
• To engineer systems for coordinated multi-cell fate decisions.

Main Methods:

• Harnessing endogenous epigenetic silencing mechanisms.
• Designing synthetic Notch receptors to control chromatin regulators KRAB and Dnmt3L.
• Constructing combinatorial input-controlled circuits for cell fate choices.
• Inverting silencing switches to achieve sustained gene activation.

Main Results:

• Developed input-controlled epigenetic switches for self-sustaining gene silencing.
• Demonstrated combinatorial inputs directing specific cell fate choices.
• Showcased inversion of switches for sustained gene activation.
• Engineered an epigenetic memory switch driving stable morphological fate changes post-transient signals.

Conclusions:

• Synthetic epigenetic circuits can induce stable, heritable gene expression changes.
• These circuits enable input-controlled, self-sustaining cell fate decisions.
• The developed epigenetic memory switch mimics developmental stability over cell divisions.
• This work advances the engineering of cell populations for coordinated fate decisions.