A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment

Area of Science:

• Developmental Biology
• Epigenetics
• Molecular Biology

Background:

• Cell fate decisions involve irreversible gene activation.
• These events are often linked to transcription factors but may also involve cis-epigenetic mechanisms.
• Bcl11b is a key gene controlling T-cell fate commitment.

Purpose of the Study:

• To investigate the mechanisms controlling Bcl11b gene activation.
• To distinguish between cis-acting and trans-acting regulatory effects on Bcl11b.
• To understand the role of cis-epigenetic regulation in cell fate transitions.

Main Methods:

• Generated mice with fluorescently tagged Bcl11b alleles.
• Utilized quantitative live microscopy to observe Bcl11b activation dynamics.
• Employed genetic perturbations and mathematical modeling.

Main Results:

• Bcl11b activation occurred after a multi-day stochastic delay, varying between cells and alleles.
• A distal enhancer regulated the rate of cis-epigenetic activation.
• Notch signaling provided a trans-acting stimulus to already activated loci.

Conclusions:

• Developmental cell fate transitions can be governed by stochastic cis-acting events at individual gene loci.
• Both cis-epigenetic regulation and trans-acting factors contribute to Bcl11b activation.
• This highlights the importance of locus-specific epigenetic control in cell fate determination.