ZNF198 stabilizes the LSD1-CoREST-HDAC1 complex on chromatin through its MYM-type zinc fingers.

Howard Hughes Medical Institute, Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
PLoS ONE (Impact Factor: 3.53). 02/2008; 3(9):e3255. DOI: 10.1371/journal.pone.0003255
Source: PubMed

ABSTRACT Histone modifications in chromatin regulate gene expression. A transcriptional co-repressor complex containing LSD1-CoREST-HDAC1 (termed LCH hereafter for simplicity) represses transcription by coordinately removing histone modifications associated with transcriptional activation. RE1-silencing transcription factor (REST) recruits LCH to the promoters of neuron-specific genes, thereby silencing their transcription in non-neuronal tissues. ZNF198 is a member of a family of MYM-type zinc finger proteins that associate with LCH. Here, we show that ZNF198-like proteins are required for the repression of E-cadherin (a gene known to be repressed by LSD1), but not REST-responsive genes. ZNF198 binds preferentially to the intact LCH ternary complex, but not its individual subunits. ZNF198- and REST-binding to the LCH complex are mutually exclusive. ZNF198 associates with chromatin independently of LCH. Furthermore, modification of HDAC1 by small ubiquitin-like modifier (SUMO) in vitro weakens its interaction with CoREST whereas sumoylation of HDAC1 stimulates its binding to ZNF198. Finally, we mapped the LCH- and HDAC1-SUMO-binding domains of ZNF198 to tandem repeats of MYM-type zinc fingers. Therefore, our results suggest that ZNF198, through its multiple protein-protein interaction interfaces, helps to maintain the intact LCH complex on specific, non-REST-responsive promoters and may also prevent SUMO-dependent dissociation of HDAC1.

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    • "In TcBuster , AeBuster1 transposase , and the mammalian Buster1 proteins , this CxxH or CLLYRH motif is part of a larger motif with the sequence CxxxC ( 28 – 29x ) CxxH / CLLYRH , which , while similar to the THAP - type Zn and MYM - type Zn finger domains ( Bessiere et al . 2008 ; Gocke and Yu 2008 ) , appears to be a novel type of zinc finger that could , in principle , coordinate a divalent cation . The second C of this expanded motif is two residues upstream from the central D of the catalytic triad of these transposases , raising the question as to whether this region of the molecule can actually participate in two different che - lations of a divalent cation . "
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    Genetics 03/2011; 188(1):45-57. DOI:10.1534/genetics.111.126813 · 4.87 Impact Factor
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    • "The intact LCH complex is maintained on specific, non- REST-responsive promoters by a zinc finger protein ZNF198 (Gocke and Yu, 2008). LSD1 interacts with androgen receptor (AR) and demethylates the repressive histone mark H3K9me1/2 to promote androgen-receptor-dependent transcription (Metzger et al., 2005). "
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    European journal of cell biology 02/2010; 89(7):557-63. DOI:10.1016/j.ejcb.2010.01.004 · 3.70 Impact Factor
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    • "In this regard, it is interesting to note that two other components of the LSD1/ CoREST1/HDAC complex, RBBP4 and ZnF198, also bind non-covalently to SUMO (Figure 4 and Hecker et al., 2006). A role for ZNF198 binding to SUMO-modified HDAC1 in regulation of LSD1/CoREST1/HDAC complex activity has been suggested (Gocke and Yu, 2008). RBBP4 is a component of the core HDAC1,2 complex (Humphrey et al., 2001) and our data raise the possibility that RBBP4/SUMO-2 interactions may regulate HDAC activity or localization beyond the LSD1/CoREST1/HDAC complex. "
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    Molecular cell 05/2009; 34(2):145-54. DOI:10.1016/j.molcel.2009.03.013 · 14.46 Impact Factor
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