Transdifferentiation. Sequential histone-modifying activities determine the robustness of transdifferentiation

Area of Science:

• Epigenetics
• Developmental Biology
• Cell Biology

Background:

• Somatic cell reprogramming occurs naturally across species.
• Understanding robust cell conversion mechanisms is crucial for regenerative medicine.
• Caenorhabditis elegans offers a model for studying natural cell plasticity.

Purpose of the Study:

• To investigate the molecular mechanisms ensuring robust transdifferentiation (Td) of hindgut cells into motor neurons in C. elegans.
• To identify key epigenetic regulators involved in invariant cell conversion.
• To compare natural Td mechanisms with in vitro cell reprogramming strategies.

Main Methods:

• Single-cell resolution analysis of postmitotic hindgut cells undergoing Td.
• Investigating the roles of histone-modifying enzymes, specifically JMJD-3.1 and the Set1 complex.
• Tracking nuclear degradation of JMJD-3.1 and its interaction with transcription factors.

Main Results:

• JMJD-3.1 (H3K27me3/me2 demethylase) and Set1 complex (H3K4 methyltransferase) cooperate for invariant hindgut cell to motor neuron Td.
• Robust Td requires stepwise histone modification activities partitioned into discrete phases.
• Nuclear degradation of JMJD-3.1 and phase-specific transcription factor interactions are critical for Td progression.

Conclusions:

• Epigenetic mechanisms involving JMJD-3.1 and Set1 orchestrate robust natural cell transdifferentiation.
• Stepwise histone modification and regulated protein degradation ensure efficient and invariant cell fate conversion.
• Findings provide insights into conserved epigenetic principles underlying both natural and induced cell reprogramming.