L3MBTL1, a Histone-Methylation-Dependent Chromatin Lock

Howard Hughes Medical Institute, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, Piscataway, NJ 08854, USA.
Cell (Impact Factor: 32.24). 07/2007; 129(5):915-28. DOI: 10.1016/j.cell.2007.03.048
Source: PubMed


Distinct histone lysine methylation marks are involved in transcriptional repression linked to the formation and maintenance of facultative heterochromatin, although the underlying mechanisms remain unclear. We demonstrate that the malignant-brain-tumor (MBT) protein L3MBTL1 is in a complex with core histones, histone H1b, HP1gamma, and Rb. The MBT domain is structurally related to protein domains that directly bind methylated histone residues. Consistent with this, we found that the L3MBTL1 MBT domains compact nucleosomal arrays dependent on mono- and dimethylation of histone H4 lysine 20 and of histone H1b lysine 26. The MBT domains bind at least two nucleosomes simultaneously, linking repression of transcription to recognition of different histone marks by L3MBTL1. Consistently, L3MBTL1 was found to negatively regulate the expression of a subset of genes regulated by E2F, a factor that interacts with Rb.

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    • "The targets also can be within one nucleosome, such as in the case of the PRC2 complex , which binds to a nucleosome through multiple contacts, including H3K27me, the H3 tail and H4 tails (Margueron et al., 2009; Murzina et al., 2008). Finally, nucleosomal targets can be spread over multiple nucleosomes, as has been shown for the SIR complex (Martino et al., 2009) and L3MBTL1 (Trojer et al., 2007). Another feature of chromatin structure that has emerged as a key recognition site for the chromatin complex is the linker DNA and the space between adjacent nucleosomes. "
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    ABSTRACT: The Rpd3S histone deacetylase complex utilizes two subunits, Eaf3 and Rco1, to recognize nucleosomes methylated at H3K36 (H3K36me) with high affinity and strong specificity. However, the chromobarrel domain of Eaf3 (CHD) that is responsible for H3K36me recognition only binds weakly and with little specificity to histone peptides. Here, using deuterium exchange mass spectrometry (DXMS), we detected conformational changes of Rpd3S upon its contact with chromatin. Interestingly, we found that the Sin3-interacting domain of Rco1 (SID) allosterically stimulates preferential binding of Eaf3 to H3K36-methylated peptides. This activation is tightly regulated by an autoinhibitory mechanism to ensure optimal multivalent engagement of Rpd3S with nucleosomes. Lastly, we identified mutations at the interface between SID and Eaf3 that do not disrupt complex integrity but severely compromise Rpd3S functions in vitro and in vivo, suggesting that the nucleosome-induced conformational changes are essential for chromatin recognition.
    Full-text · Article · Jan 2015 · Cell Reports
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    • "This article is protected by copyright . All rights reserved . 36 L3MBTL1 is a transcriptional repressor that binds monomethyl H3K4 or dimethylated H4K20 through its three MBT ( malignant brain tumor ) domains to effect the compaction of nucleosomes ( Trojer et al . , 2007 ) . L3MBTL1 interacts with TP53 that is monomethylated at Lys382 by SET8 and is recruited to TP53 target genes to repress TP53 - mediated induction under basal conditions ( Fig . 5 ) . In vitro , L3MBT1 can bind a dimethylated Lys382 peptide with equal affinity ( West et al . , 2010 ) . In response to DNA damage , the levels of SET8 and"
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    ABSTRACT: The wild-type human p53 (TP53) tumor suppressor can be posttranslationally modified at over 60 of its 393 residues. These modifications contribute to changes in TP53 stability and in its activity as a transcription factor in response to a wide variety of intrinsic and extrinsic stresses in part through regulation of protein-protein and protein-DNA interactions. The TP53 gene frequently is mutated in cancers, and in contrast to most other tumor suppressors the mutations are mostly missense often resulting in the accumulation of mutant protein, which may have novel or altered functions. Most mutant TP53s can be posttranslationally modified at the same residues as in wild-type TP53. Strikingly, however, codons for modified residues are rarely mutated in human tumors, suggesting that TP53 modifications are not essential for tumor suppression activity. Nevertheless, these modifications might alter mutant TP53 activity and contribute to a gain-of-function leading to increased metastasis and tumor progression. Furthermore, many of the signal transduction pathways that result in TP53 modifications are altered or disrupted in cancers. Understanding the signaling pathways that result in TP53 modification and the functions of these modifications in both wild-type TP53 and its many mutant forms may contribute to more effective cancer therapies. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2014 · Human Mutation
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    • "Importantly, the isolated 3xMBT domain forms no significant contacts with the side chains of amino acids surrounding the methylated residue, providing a structural basis for sequence-independent binding to methyllysine. The specificity of L3MBTL1 for physiologically relevant methylated proteins such as H4 and Rb is thought to be conferred by the 3xMBT binding to methyllysine in combination with nonmethyl-sensitive interactions mediated by regions outside of the 3xMBT domain (Trojer et al., 2007). "
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    ABSTRACT: Lysine methylation of histone proteins regulates chromatin dynamics and plays important roles in diverse physiological and pathological processes. However, beyond histone proteins, the proteome-wide extent of lysine methylation remains largely unknown. We have engineered the naturally occurring MBT domain repeats of L3MBTL1 to serve as a universal affinity reagent for detecting, enriching, and identifying proteins carrying a mono- or dimethylated lysine. The domain is broadly specific for methylated lysine ("pan-specific") and can be applied to any biological system. We have used our approach to demonstrate that SIRT1 is a substrate of the methyltransferase G9a both in vitro and in cells, to perform proteome-wide detection and enrichment of methylated proteins, and to identify candidate in-cell substrates of G9a and the related methyltransferase GLP. Together, our results demonstrate a powerful new approach for global and quantitative analysis of methylated lysine, and they represent the first systems biology understanding of lysine methylation.
    Full-text · Article · Apr 2013 · Molecular cell
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