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Sequential histone-modifying activities determine the robustness of transdifferentiation

Science  15 Aug 2014:
Vol. 345, Issue 6198, pp. 826-829
DOI: 10.1126/science.1255885

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Epigenetics direct transdifferentiation

To make an entire animal, many and varied cell types form and interact. Some of these differentiated cells take a U-turn and can de-differentiate or transdifferentiate to another cell fate. Although relatively rare in nature, Zuryn et al. followed such a program in the tiny roundworm Caenorhabditis elegans, where a rectal cell–to–motor neuron conversion is seen. Transcription factors with conserved roles in cell plasticity and terminal fate selection partner up with specific histone-modifying enzymes in discrete steps to specify separate sequential phases of cell identity.

Science, this issue p. 826

Abstract

Natural interconversions between distinct somatic cell types have been reported in species as diverse as jellyfish and mice. The efficiency and reproducibility of some reprogramming events represent unexploited avenues in which to probe mechanisms that ensure robust cell conversion. We report that a conserved H3K27me3/me2 demethylase, JMJD-3.1, and the H3K4 methyltransferase Set1 complex cooperate to ensure invariant transdifferentiation (Td) of postmitotic Caenorhabditis elegans hindgut cells into motor neurons. At single-cell resolution, robust conversion requires stepwise histone-modifying activities, functionally partitioned into discrete phases of Td through nuclear degradation of JMJD-3.1 and phase-specific interactions with transcription factors that have conserved roles in cell plasticity and terminal fate selection. Our results draw parallels between epigenetic mechanisms underlying robust Td in nature and efficient cell reprogramming in vitro.

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