NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis

Department of Pathology, University of California at San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Nature Cell Biology (Impact Factor: 19.68). 08/2007; 9(7):804-12. DOI: 10.1038/ncb1608
Source: PubMed


Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus.

Download full-text


Available from: Gang Greg Wang, Jan 23, 2015
  • Source
    • "Curiously, a similar configuration is found in patients with acute myeloblastic leukemia, with the fusion protein N-terminal NUP98-MLL acquiring a H3K4 methyltransferase ability through the SET domain present in MLL39. Similar observations support the association of SET with Nup9840, for instance the fusion of Nup98 to NSD1 (another SET-containing histone methyltransferase)41. The Nup43-DHX15 helicase association found in uncharacterized proteins of multiple insect species, for instance Nasonia vitripennis (GI:345482402), is consistent with the presence of a Werner helicase interacting protein in the Y-complex42 and DDX10 in leukemia43, while it is also detected in Oct4 interactions along with Nup4331 and very strong correlations with multiple Y-Nups (Supplementary Table 3, Figure 4). "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is growing evidence for the involvement of Y-complex nucleoporins (Y-Nups) in cellular processes beyond the inner core of nuclear pores of eukaryotes. To comprehensively assess the range of possible functions of Y-Nups, we delimit their structural and functional properties by high-specificity sequence profiles and tissue-specific expression patterns. Our analysis establishes the presence of Y-Nups across eukaryotes with novel composite domain architectures, supporting new moonlighting functions in DNA repair, RNA processing, signaling and mitotic control. Y-Nups associated with a select subset of the discovered domains are found to be under tight coordinated regulation across diverse human and mouse cell types and tissues, strongly implying that they function in conjunction with the nuclear pore. Collectively, our results unearth an expanded network of Y-Nup interactions, thus supporting the emerging view of the Y-complex as a dynamic protein assembly with diverse functional roles in the cell.
    Full-text · Article · Apr 2014 · Scientific Reports
  • Source
    • "Furthermore, via chromosomal translocation, it forms fusion proteins in cancers, and nearly 5% of the human AML patients contain the NUP98-NSD1 fusion oncoprotein created by the fusion of NSD1 to the nucleoporin gene (NUP98). The NUP98-NSD1 fusion protein targets H3K36 methylation activity to the Hox-A locus and enhances its expression (Wang et al., 2007). In addition, the NSD1 gene promoter is silenced by hypermethylation in human neuroblastomas and glioblastoma cells, and loss of NSD1 leads to an enhanced expression of the ME1S1 oncogene (Berdasco et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The nuclear receptor binding SET [su(var) 3-9, enhancer of zeste, trithorax] domain-containing protein 1 (NSD1) protein lysine methyltransferase (PKMT) was known to methylate histone H3 lysine 36 (H3K36). We show here that NSD1 prefers aromatic, hydrophobic, and basic residues at the -2, -1 and +2, and +1 sites of its substrate peptide, respectively. We show methylation of 25 nonhistone peptide substrates by NSD1, two of which were (weakly) methylated at the protein level, suggesting that unstructured protein regions are preferred NSD1 substrates. Methylation of H4K20 and p65 was not observed. We discovered strong methylation of H1.5 K168, which represents the best NSD1 substrate protein identified so far, and methylation of H4K44 which was weaker than H3K36. Furthermore, we show that Sotos mutations in the SET domain of NSD1 inactivate the enzyme. Our results illustrate the importance of specificity analyses of PKMTs for understanding protein lysine methylation signaling pathways.
    Full-text · Article · Jan 2014 · Chemistry & biology
  • Source
    • "Interestingly , there are also some factors representing epigenetic fea - tures of hESCs ( Kashyap et al . , 2009 ) such as Ing2 NSD1 , Jarid , Hox and Olfml2 among the predicted genes . Nup98 fusions to the NSD1 H3K36 methyltransferase and KDM5A induce leukemia ( Wang et al . , 2007 , 2009 ) . In hESCs , KDM5B , histone H3 trimethyl lysine 4 ( H3K4me3 ) demethylase , is a downstream NANOG target and contributes to ESCs self - renewal . Additionally KDM5B is recruited to H3K36me3 in intra - genic regions of hESCs ( Xie et al . , 2011 ) . ING2 interacts to H3K4me3 during DNA damage and active gene repression ( Shi et"
    [Show abstract] [Hide abstract]
    ABSTRACT: Self-proliferation and differentiation into distinct cell types have been made stem cell as a promising target for regenerative medicine. Several key genes can regulate self-renewal and pluripotency of embryonic stem cells (hESCs). They work together and build a transcriptional hierarchy. Coexpression and coregulation of genes control by common regulatory elements on the promoter regions. Consequently, distinct organization and combination of transcription factor binding sites (TFBSs modules) on promoter regions, in view of order and distance, leads to a common specific expression pattern within a set of genes. To gain insights into transcriptional regulation of hESCs, we selected promoter regions of eleven common expressed hESC genes including SOX2, LIN28, STAT3, NANOG, LEFTB, TDGF1, POU5F1, FOXD3, TERF1, REX1 and GDF3 to predict activating regulatory modules on promoters and discover key corresponding transcription factors. Then, promoter regions in human genome were explored for modules and 328 genes containing the same modules were detected. Using microarray data, we verified that 102 of 328 genes commonly upregulate in hESCs. Also, using output data of DNA-Protein interaction assays, we found that 42 of all predicted genes are targets of SOX2, NANOG and POU5F1 . Additionally, a protein interaction network of hESC genes was constructed based on biological processes and interestingly, 126 downregulated genes along with upregulated ones identified by promoter analysis were predicted in the network. Based on the results, we suggest that the identified genes, coregulating with common hESC genes, represent a novel approach for gene discovery based on whole genome promoter analysis irrespective of gene expression. Altogether, promoter profiling can be used to expand hESC transcriptional regulatory circuitry by analysis of shared functional sequences between genes. This approach provides a clear image on underlying regulatory mechanism of gene expression profile and offers a novel approach in designing gene networks of stem cell.
    Full-text · Article · Sep 2013 · Gene
Show more