1. Laboratory of Chromatin Biology,
2. Laboratory of Molecular Vertebrate Embryology, and
3. Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
4. Laboratory of Molecular Cell Biology, National Cancer Institute, NIH, Bethesda, Maryland 20814, USA
5. Institute of Biomedical Research, University of Birmingham, Edgbaston B15 2TT, UK

Correspondence to: Carl Wu⁴C. David Allis¹ Correspondence and requests for materials should be addressed to C.D.A. (Email: alliscd@rockefeller.edu), and requests for materials relating to Drosophila and mammalian NURF to C.W. (Email: carlwu@helix.nih.gov).

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 genes^{1, 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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