Article

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

ABSTRACT

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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    • "lid and Kdm2 genetically interact in Drosophila (Li et al. 2010). LID specifically removes H3K4me3 (Eissenberg et al. 2007; Lee et al. 2007; Secombe et al. 2007; Lloret-Llinares et al. 2008). LID is critical for Drosophila viability and development (Gildea et al. 2000; Li et al. 2010). "
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    ABSTRACT: Histone methylation levels, which are determined by the action of both histone demethylases and methyltransferases, impact multiple biological processes by affecting gene expression activity. Methionine metabolism generates the major methyl donor S-adenosylmethionine (SAM) for histone methylation. The functions of methionine metabolic enzymes in regulating biological processes as well as the interaction between the methionine pathway and histone methylation, however, are still not fully understood. Here, we report that reduced levels of some enzymes involved in methionine metabolism and histone demethylases lead to lethality as well as wing development and cell proliferation defects in Drosophila melanogaster. Additionally, disruption of methionine metabolism can directly affect histone methylation levels. Reduction of little imaginal discs (LID) histone demethylase, but not lysine-specific demethylase 2 (KDM2) demethylase, is able to counter the effects on histone methylation due to reduction of SAM synthetase (SAM-S). Taken together, these results reveal an essential role of key enzymes that control methionine metabolism and histone methylation. Additionally, these findings are an indication of a strong connection between metabolism and epigenetics.
    Preview · Article · Nov 2015 · G3-Genes Genomes Genetics
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    • "RESULTS Lid acts cell autonomously in the germline to maintain GSC number at the niche The lid gene encodes a histone demethylase that has been reported to specifically demethylate H3K4me3 in vivo (Eissenberg et al., 2007; Lee et al., 2007). To confirm the function of Lid as a specific H3K4me3 demethylase in the testis, we used a strong loss-offunction allele of lid (lid 10424 ) (Gildea et al., 2000; Li et al., 2010). "
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    ABSTRACT: Signaling pathways and epigenetic mechanisms have both been shown to play essential roles in regulating stem cell activity. While the role of either mechanism in this regulation is well established in multiple stem cell lineages, how the two mechanisms interact to regulate stem cell activity is not as well understood. Here we report that in the Drosophila testis, an H3K4me3-specific histone demethylase encoded by little imaginal discs (lid) maintains germline stem cell (GSC) mitotic index and prevents GSC premature differentiation. Lid is required in germ cells for proper expression of the Stat92E transcription factor, the downstream effector of the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway. Our findings support a germ cell autonomous role for the JAK-STAT pathway in maintaining GSCs and place Lid as an upstream regulator of this pathway. Our study provides new insights into the biological functions of a histone demethylase in vivo and sheds light on the interaction between epigenetic mechanisms and signaling pathways in regulating stem cell activities.
    Preview · Article · Oct 2015 · Biology Open
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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.
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