DNA-specific “erasers” of epigenetic memory involving chromatin remodeling

Multifactorial traits are the result of the combined contribution from genes (DNA sequence), epigenetic effects (chromosomal events including DNA methylation, RNA-interference, histone modifications, and chromatin remodeling), and the environment. These two papers describe events involving histone modifications that lead to chromatin-remodeling in the tiny flowering mustard plant, Arabidopsis thaliana. How epigenetic regulators find their specific targets remains a challenging question. Two parallel studiesshow that REF6, a plant H3K27me3 demethylase, binds a specific DNA motif via its zinc-finger domains and recruits the SWI/SNF-type ATPase BRAHMA, demonstrating a sequence-specific recruitment mechanism for a chromatin-modifying complex.

SWI/SNF-type chromatin remodelers, such as BRAHMA (BRM), and H3K27 demethylases are both known to have active roles in regulating gene expression at the chromatin

level, but how they are recruited to specific genomic sites remains largely unknown. In the first article [attached; pp 687–693], authors demonstrate that REF6 (RELATIVE OF EARLY FLOWERING-6), a plant-unique H3K27 demethylase, targets genomic loci containing a CTCTGYTY motif via its zinc-finger domains and facilitates recruitment of BRM.

Genome-wide analyses showed that REF6 colocalizes with BRM at many genomic sites having the CTCTGYTY motif. Loss of REF6 results in decreased BRM occupancy at BRM–REF6 co-targets. Moreover, REF6 in vitro directly binds to the CTCTGYTY motif, and deletion of the motif from a target gene renders it inaccessible to REF6 in the intact plant. Authors also provide evidence that, when these zinc-finger domains are deleted, REF6 loses its genomic targeting ability. These results identify a new genomic targeting mechanism for an H3K27 demethylase and demonstrate its key role in recruiting the BRM chromatin remodeler.

REF6 is also known to counteract Polycomb-mediated gene silencing by removing methyl groups from trimethylated histone H3 lysine 27 (H3K27me3) in hundreds of genes in Arabidopsis thaliana. In the second article [attached, pp 694-699], authors show that REF6 function and genome-wide targeting require its four Cys2His2  zinc fingers, which directly recognize a CTCTGYTY motif. Motifs bound by REF6 tend to cluster and reside in loci with active chromatin states. Furthermore, REF6 targets CUC1 (CUP-SHAPED COTYLEDON-1), which harbors CTCTGYTY motifs, to modulate H3K27me3 levels and activate CUC1 expression. Loss of REF6 causes CUC1 repression and defects in cotyledon separation. In contrast, REF6 does not bind CUC2, encoding a close homolog of CUC1 that lacks the CTCTGYTY motif. Collectively, these results identify a new targeting mechanism of an H3K27 demethylase to counteract Polycomb-mediated gene silencing that regulates plant development, including organ b

Nat Genet   June 2o16;  48: 687-693 & 694–699 (articles)  and  pp 591-592 (ed.)

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