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A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling

Abstract

Lysine methylation of histones is recognized as an important component of an epigenetic indexing system demarcating transcriptionally active and inactive chromatin domains. Trimethylation of histone H3 lysine 4 (H3K4me3) marks transcription start sites of virtually all active genes1,2,3,4. Recently, we reported that the WD40-repeat protein WDR5 is important for global levels of H3K4me3 and control of HOX gene expression5. Here we show that a plant homeodomain (PHD) finger of nucleosome remodelling factor (NURF), an ISWI-containing ATP-dependent chromatin-remodelling complex, mediates a direct preferential association with H3K4me3 tails. Depletion of H3K4me3 causes partial release of the NURF subunit, BPTF (bromodomain and PHD finger transcription factor), from chromatin and defective recruitment of the associated ATPase, SNF2L (also known as ISWI and SMARCA1), to the HOXC8 promoter. Loss of BPTF in Xenopus embryos mimics WDR5 loss-of-function phenotypes, and compromises spatial control of Hox gene expression. These results strongly suggest that WDR5 and NURF function in a common biological pathway in vivo, and that NURF-mediated ATP-dependent chromatin remodelling is directly coupled to H3K4 trimethylation to maintain Hox gene expression patterns during development. We also identify a previously unknown function for the PHD finger as a highly specialized methyl-lysine-binding domain.

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Figure 1: Human and Drosophila NURF specifically associate with histone H3 trimethylated at K4.
Figure 2: The bromodomain-proximal PHD finger of BPTF/NURF301 binds to H3 K4me3.
Figure 3: WDR5 regulates BPTF chromatin association.
Figure 4: Loss of BPTF phenocopies loss of WDR5 in axial, gut and blood defects during Xenopus development.

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Acknowledgements

We thank E. Bernstein, W. Herr and E. Duncan for critical reading of the manuscript, O. Gozani for communicating unpublished results, and D. Reinberg, W. Herr, R. Roeder and J. Tamkun for CHD1, WDR5, MLL and ISWI antibodies, respectively. T.S. thanks A. H. Brivanlou for support. J.W. is a D. Runyon CRF Fellow, T.A.M. is a Canadian Institutes of Health Research Fellow, and J.L is an ACS Postdoctoral Research Fellow. C.W., J.L. and H.X. are supported by the US National Cancer Institute Intramural Research Program, and S.Y.K. and P.B. are supported by the BBSRC. C.D.A. acknowledges a MERIT Award from the NIH.

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Correspondence to Carl Wu or C. David Allis.

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Wysocka, J., Swigut, T., Xiao, H. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006). https://doi.org/10.1038/nature04815

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