Methylation of histone 3 lysine 4 (H3K4) is largely associated with promoters and enhancers of actively transcribed genes and is finely regulated during development by the action of histone methyltransferases and demethylases. H3K4me3 demethylases of the KDM5 family have been previously implicated in development, but how the regulation of H3K4me3 level controls developmental processes is not fully established. Here, we show that the H3K4 demethylase RBR-2, the unique member of the KDM5 family in C. elegans, acts cell-autonomously and in a catalytic-dependent manner to control vulva precursor cells fate acquisition, by promoting the LIN-12/Notch pathway. Using genome-wide approaches, we show that RBR-2 reduces the H3K4me3 level at transcription start sites (TSSs) and in regions upstream of the TSSs, and acts both as a transcription repressor and activator. Analysis of the lin-11 genetic locus, a direct RBR-2 target gene required for vulva precursor cell fate acquisition, shows that RBR-2 controls the epigenetic signature of the lin-11 vulva-specific enhancer and lin-11 expression, providing in vivo evidence that RBR-2 can positively regulate transcription and cell fate acquisition by controlling enhancer activity.
The authors declare no competing or financial interests.
Y.C.L., L.M., C.F., J.P., T.R.M., C.K., G.W. and A.E.S. designed the study, collected the data and performed the analysis. Y.C.L. and A.E.S. wrote the manuscript.
This work was supported by the Centre for Epigenetics at Københavns Universitet (Copenhagen University), Danmarks Grundforskningsfond (The Danish National Research Foundation) [grant number DNRF82 to A.E.S] and the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation) [grant number PBBSP3_141371 to Y.C.L.]. This research was also supported in part by Suomen Akatemia (Academy of Finland) [grant number MYRG2015-00231-FHS G.W].
ChIP-seq data are available at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi under accession number GSE86937.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.139139.supplemental
- Received April 27, 2016.
- Accepted August 20, 2016.