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IGDB Scientists Revealed New Mechanism of Histone Demethylase Genome-wide Targeting

In metazoans and plants, trimethylation of histone H3 lysine27 (H3K27me3) facilitates the maintenance of developmentally regulated genes in a transcriptionally repressed state. The establishment and the removal of H3K27me3 at specific genes are therefore critically important for normal development. The RELATIVE OF EARLY FLOWERING 6 protein (REF6, also known as JMJ12) specifically demethylates H3K27me3 at its target loci for transcriptional activation. Loss of REF6 leads to the ectopic accumulation of H3K27me3 at hundreds of genes in seedlings, as well as a number of developmental phenotypes. However, how REF6 is targeted to specific genes remains unknown.


The research group led by Dr. CAO Xiaofeng at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, found that REF6 function and genome-wide targeting require its four Cys2-His2 zinc fingers, which directly recognize the CTCTGYTY motif. Analyzing the genome-wide distribution of the motif, they found REF6 prefer to bind motifs clustering together and locating in loci with active chromatin states.


In addition, they found REF6 involves cotyledon separation by directly regulating the CUP-SHAPED COTYLEDON 1 (CUC1) gene, which harbors six CTCTGYTY-motifs. The proper levels of H3K27me3 and activation of CUC1 require REF6. By contrast, REF6 does not bind the close homolog CUC2, which lacks the CTCTGYTY motif. Consistent with its effect on CUC1, mutation of REF6 causes defects in cotyledon separation.


This study revealed a novel targeting mechanism of an H3K27me3 demethylase that regulates plant development, including organ boundary formation. In addition to REF6 and its close Arabidopsis homolog EARLY FLOWERING 6 (ELF6, also known as JMJ11), many JmjC domain-containing proteins in other plant species also contain tandem arrays of C2H2-ZnF domains. It will be of interest to determine the sequence specificities of the C2H2-ZnF domains in other JmjC domain-containing proteins, and explore how these proteins may function at specific genes to regulate local histone methylation levels.


The work entitled “REF6 recognizes a specific DNA sequence to demethylate H3K27me3 and regulate organ boundary formation in Arabidopsis” was published on Nature Genetics on April 25, 2016 (DOI:10.1038/ng.3556). This work was supported by the grants from National Basic Research Program of China, the National Natural Science Foundation of China and the State Key Laboratory of Plant Genomics.



Model for REF6 targeting. REF6 binds the CTCTGYTY-motif through the C2H2-ZnF cluster and removes local H3K27me3 methylation. Genes containing clusters of CTCTGYTY-motifs recruit REF6 more efficiently (upper panel), while motifs in heterochromatic regions cannot recruit REF6 (bottom panel). (Image by IGDB)


Author Contacts:

Dr. CAO Xiaofeng

Institute of Genetics and Developmental Biology, Chinese Academy of Sciences