L3MBTL1, a histone-methylation-dependent chromatin lock.
ABSTRACT 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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ABSTRACT: Epigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell populations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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ABSTRACT: Histone posttranslational modifications (PTMs) are important cellular signals that can be read by a large repertoire of PTM recognition modules (Jenuwein and Allis, 2001) to direct many DNA template-dependent activities. These PTM reader domains have been well documented for their ability to distinguish differently modified residues or unmodified residues (Kouzarides, 2007 and Yun et al., 2011). A recent study showed that the tandem bromo-PWWP domain of a tumor-suppressor protein ZMYND11 preferentially binds to histone H3.3 that is methylated at lysine 36, but not to methylated H3.1 (Wen et al., 2014), suggesting that the reader domain can even select for modified histone variants. The prevalent notion is that each chromatin regulator is equipped with a different combination of the PTM reading modules (Ruthenburg et al., 2007), which allows complexes that engage with nucleosomes in a multivalent fashion to achieve robust binding and high specificity (Yun et al., 2011). The nucleosomal surface targets for these readers can be on one histone; for instance, Trim24 utilizes a tandem plant homeobox domain (PHD)-Bromo domain to recognize H3K4me0 and H3K23Ac on the same histone tail (Tsai et al., 2010). 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 and 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. Three examples reported so far are the following: the PRC2 histone methyltransferase complex prefers dense nucleosome arrays (Yuan et al., 2012); the Rpd3S histone deacetylase complex favors dinucleosome units that are spaced about 30–40 bp apart (Lee et al., 2013); and the SWR1 remodeler targets the longer linker and nucleosome-free regions (Ranjan et al., 2013). However, how combinations of these rather static interactions are coordinated to achieve synergetic binding remains largely unknown.Cell Reports 01/2015; 28(2). DOI:10.1016/j.celrep.2014.12.027 · 7.21 Impact Factor
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ABSTRACT: Abstract Gene transcription is tightly regulated at different levels to ensure that the transcriptome of the cell is appropriate for developmental stage and cell type. The chromatin state in which a gene is embedded determines its expression level to a large extent. Activation or repression of transcription is typically accomplished by the recruitment of chromatin-associated multisubunit protein complexes that combine several molecular tools, such as histone-binding and chromatin-modifying activities. Recent biochemical purifications of such complexes have revealed a substantial diversity. On the one hand, complexes that were thought to be unique have been revealed to be part of large complex families. On the other hand, protein subunits that were thought to only exist in separate complexes have been shown to coexist in novel assemblies. In this review we discuss our current knowledge of repressor complexes that contain MBT domain proteins and/or the CoREST co-repressor and use them as a paradigm to illustrate the unexpected heterogeneity and tool sharing of chromatin regulating protein complexes. These recent insights also challenge the ways we define and think about protein complexes in general.Epigenetics: official journal of the DNA Methylation Society 11/2014; DOI:10.4161/15592294.2014.971580 · 5.11 Impact Factor