Lee, N. et al. The trithorax-group protein Lid is a histone H3 trimethyl-Lys4 demethylase. Nat. Struct. Mol. Biol. 14, 341-343

Memorial Sloan-Kettering Cancer Center, New York, New York, United States
Nature Structural & Molecular Biology (Impact Factor: 13.31). 05/2007; 14(4):341-3. DOI: 10.1038/nsmb1216
Source: PubMed


Recent studies have demonstrated that histone methylation can be dynamically regulated through active demethylation. However, no demethylase specific to histone H3 trimethyl-Lys4 (H3K4me3) has been identified. Here we report that the Drosophila melanogaster protein 'little imaginal discs' (Lid), a JmjC domain-containing trithorax group protein, can demethylate H3K4me3. Consistent with its genetic classification, Lid positively regulates Hox gene expression in S2 cells.

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Available from: Hediye Erdjument-Bromage, May 22, 2014
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    • "KDM5B belongs to the KDM5/JARID1 family, which catalyzes the removal of methyl groups from tri-, di-, and monomethylated lysine 4 of histone H3 (H3K4me3/2/1), and also includes KDM5A/ RBP2, KDM5C/SMCX, and KDM5D/SMCY in mammals (Christensen et al., 2007; Iwase et al., 2007; Klose et al., 2007; Yamane et al., 2007). Both fly and yeast have a single ortholog of KDM5: the Drosophila Little imaginal disks (Lid) and S. cerevisiae Jhd2p/ Yjr119Cp, respectively (Eissenberg et al., 2007; Lee et al., 2007; Liang et al., 2007; Secombe et al., 2007; Seward et al., 2007). The KDM5 proteins have a highly conserved domain architecture . "
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    ABSTRACT: The histone lysine demethylase KDM5B regulates gene transcription and cell differentiation and is implicated in carcinogenesis. It contains multiple conserved chromatin-associated domains, including three PHD fingers of unknown function. Here, we show that the first and third, but not the second, PHD fingers of KDM5B possess histone binding activities. The PHD1 finger is highly specific for unmodified histone H3 (H3K4me0), whereas the PHD3 finger shows preference for the trimethylated histone mark H3K4me3. RNA-seq analysis indicates that KDM5B functions as a transcriptional repressor for genes involved in inflammatory responses, cell proliferation, adhesion, and migration. Biochemical analysis reveals that KDM5B associates with components of the nucleosome remodeling and deacetylase (NuRD) complex and may cooperate with the histone deacetylase 1 (HDAC1) in gene repression. KDM5B is downregulated in triple-negative breast cancer relative to estrogen-receptor-positive breast cancer. Overexpression of KDM5B in the MDA-MB 231 breast cancer cells suppresses cell migration and invasion, and the PHD1-H3K4me0 interaction is essential for inhibiting migration. These findings highlight tumor-suppressive functions of KDM5B in triple-negative breast cancer cells and suggest a multivalent mechanism for KDM5B-mediated transcriptional regulation.
    Cell Reports 01/2014; 6(2). DOI:10.1016/j.celrep.2013.12.021 · 8.36 Impact Factor
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    • "On the contrary, recent studies have demonstrated that histone methylation can be dynamically regulated through active demethylation. In particular, genetic studies in Drosophila have demonstrated that little imaginal discs (Lid), a Jumonji C domain-containing TrxG protein, can demethylate the trimethylated form of H3K4, thus removing the activation marks and facilitating gene silencing[123]. The four human orthologs of the Lid protein (RBP2/JARID1A, PLU-1/JARID1B, SMCX, and SMCY) belong to the JARID1/KDM5 protein family and show high sequence conservation. "
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    ABSTRACT: During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
    Ai zheng = Aizheng = Chinese journal of cancer 07/2013; 33(2). DOI:10.5732/cjc.013.10040 · 2.16 Impact Factor
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    • "In addition, in Drosophila, ASH2 was recently shown to localize at TSS (26). On the other hand, two H3K4 KDMs have been identified in Drosophila, dKDM1/LSD1/SU(VAR)3-3 that demethylates H3K4me and H3K4me2, but not H3K4me3 (27), and the Jumonji-domain containing protein dKDM5/LID, which effectively demethylates H3K4me3 (28–31). "
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    ABSTRACT: H3K4me3 is a histone modification that accumulates at the transcription-start site (TSS) of active genes and is known to be important for transcription activation. The way in which H3K4me3 is regulated at TSS and the actual molecular basis of its contribution to transcription remain largely unanswered. To address these questions, we have analyzed the contribution of dKDM5/LID, the main H3K4me3 demethylase in Drosophila, to the regulation of the pattern of H3K4me3. ChIP-seq results show that, at developmental genes, dKDM5/LID localizes at TSS and regulates H3K4me3. dKDM5/LID target genes are highly transcribed and enriched in active RNApol II and H3K36me3, suggesting a positive contribution to transcription. Expression-profiling show that, though weakly, dKDM5/LID target genes are significantly downregulated upon dKDM5/LID depletion. Furthermore, dKDM5/LID depletion results in decreased RNApol II occupancy, particularly by the promoter-proximal Pol llo(ser5) form. Our results also show that ASH2, an evolutionarily conserved factor that locates at TSS and is required for H3K4me3, binds and positively regulates dKDM5/LID target genes. However, dKDM5/LID and ASH2 do not bind simultaneously and recognize different chromatin states, enriched in H3K4me3 and not, respectively. These results indicate that, at developmental genes, dKDM5/LID and ASH2 coordinately regulate H3K4me3 at TSS and that this dynamic regulation contributes to transcription.
    Nucleic Acids Research 08/2012; 40(19):9493-505. DOI:10.1093/nar/gks773 · 9.11 Impact Factor
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