The C. elegans H3K27 Demethylase UTX-1 Is Essential for Normal Development, Independent of Its Enzymatic Activity

Epigenetic modifications influence gene expression and provide a unique mechanism for fine-tuning cellular differentiation and development in multicellular organisms. Here we report on the biological functions of UTX-1, the Caenorhabditis elegans homologue of mammalian UTX, a histone demethylase specific for H3K27me2/3. We demonstrate that utx-1 is an essential gene that is required for correct embryonic and postembryonic development. Consistent with its homology to UTX, UTX-1 regulates global levels of H3K27me2/3 in C. elegans. Surprisingly, we found that the catalytic activity is not required for the developmental function of this protein. Biochemical analysis identified UTX-1 as a component of a complex that includes SET-16(MLL), and genetic analysis indicates that the defects associated with loss of UTX-1 are likely mediated by compromised SET-16/UTX-1 complex activity. Taken together, these results demonstrate that UTX-1 is required for many aspects of nematode development; but, unexpectedly, this function is independent of its enzymatic activity.

Author Summary Chromatin organization influences gene expression, and its regulation is crucial to achieve correct cellular differentiation and development in multicellular organisms. Histone demethylases are among several factors responsible for regulating chromatin dynamics. Here we report on the biological functions of UTX-1, the C. elegans homologue of the mammalian histone demethylase UTX, which specifically catalyzes the demethylation of di- and tri-methylated lysine 27 of histone H3 (H3K27me2/3). Indeed, we demonstrate that UTX-1 regulates global levels of H3K27me2/3 in C. elegans, a mark generally associated with silencing of gene expression. We also show that utx-1 is an essential gene that is required for correct embryonic and postembryonic development. Specifically, the loss of utx-1 results in developmental defects, sterility, and embryonic lethality. Surprisingly, our data show that the catalytic activity of UTX-1 is not required for its developmental functions. Our biochemical and genetic analyses indicate that loss of UTX-1 compromises the activity of the SET-16(MLL) complex, which UTX-1 is an integral part of. Taken together, these results demonstrate that UTX-1 plays an essential role in development independent of its enzymatic activity.