Removal of Polycomb repressive complex 2 makes C. elegans germ cells susceptible to direct conversion into specific somatic cell types.

How specific cell types can be directly converted into other distinct cell types is a matter of intense investigation with wide-ranging basic and biomedical implications. Here, we show that removal of the histone 3 lysine 27 (H3K27) methyltransferase Polycomb repressor complex 2 (PRC2) permits ectopically expressed, neuron-type-specific transcription factors ("terminal selectors") to convert Caenorhabditis elegans germ cells directly into specific neuron types. Terminal-selector-induced germ-cell-to-neuron conversion can be observed not only upon genome-wide loss of H3K27 methylation in PRC2(-) animals but also upon genome-wide redistribution of H3K27 methylation patterns in animals that lack the H3K36 methyltransferase MES-4. Manipulation of the H3K27 methylation status not only permits conversion of germ cells into neurons but also permits hlh-1/MyoD-dependent conversion of germ cells into muscle cells, indicating that PRC2 protects the germline from the aberrant execution of multiple distinct somatic differentiation programs. Taken together, our findings demonstrate that the normally multistep process of development from a germ cell via a zygote to a terminally differentiated somatic cell type can be short-cut by providing an appropriate terminal selector transcription factor and manipulating histone methylation patterns.