Ng, H.H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat. Genet. 23, 58-61

Institute of Cell and Molecular Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, UK.
Nature Genetics (Impact Factor: 29.35). 10/1999; 23(1):58-61. DOI: 10.1038/12659
Source: PubMed


Mammalian DNA is methylated at many CpG dinucleotides. The biological consequences of methylation are mediated by a family of methyl-CpG binding proteins. The best characterized family member is MeCP2, a transcriptional repressor that recruits histone deacetylases. Our report concerns MBD2, which can bind methylated DNA in vivo and in vitro and has been reported to actively demethylate DNA (ref. 8). As DNA methylation causes gene silencing, the MBD2 demethylase is a candidate transcriptional activator. Using specific antibodies, however, we find here that MBD2 in HeLa cells is associated with histone deacetylase (HDAC) in the MeCP1 repressor complex. An affinity-purified HDAC1 corepressor complex also contains MBD2, suggesting that MeCP1 corresponds to a fraction of this complex. Exogenous MBD2 represses transcription in a transient assay, and repression can be relieved by the deacetylase inhibitor trichostatin A (TSA; ref. 12). In our hands, MBD2 does not demethylate DNA. Our data suggest that HeLa cells, which lack the known methylation-dependent repressor MeCP2, use an alternative pathway involving MBD2 to silence methylated genes.

Download full-text


Available from: Hediye Erdjument-Bromage, May 01, 2015
16 Reads
  • Source
    • "In the indirect mechanism, methyl-CpG binding domain (MBD) proteins such as MeCP2, MBD1, MBD2, MBD3, and MBD4 " read " the methylation marks and bind to the methylated DNA (Bird, 2001; Bird & Wolffe, 1999; Hashimshony, Zhang, Keshet, Bustin, & Cedar, 2003; Kadonaga, 1998; Li, 2002; Nan et al., 1998). These MBD proteins affect chromatin condensation by recruiting coproteins such as SIN3A and histone-modifying enzymes, leading to chromatin compaction and transcriptional repression (Ernst et al., 2011; Ettig, Kepper, Stehr, Wedemann, & Rippe, 2011; Jones et al., 1998; Ng et al., 1999; Voltz, Trylska, Calimet, Smith, & Langowski, 2012). An important concept is that global levels of DNA methylation and gene-specific DNA methylation profiles are dynamic and vary spatially and temporally throughout life, especially during epigenetic remodeling in early development. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adaptation to environmental changes is based on the perpetual generation of new phenotypes. Modern biology has focused on the role of epigenetic mechanisms in facilitating the adaptation of organisms to changing environments through alterations in gene expression. Inherited and/or acquired epigenetic factors are relatively stable and have regulatory roles in numerous genomic activities that translate into phenotypic outcomes. Evidence that dietary and pharmacological interventions have the potential to reverse environment-induced modification of epigenetic states (e.g., early life experience, nutrition, medication, infection) has provided an additional stimulus for understanding the biological basis of individual differences in cognitive abilities and disorders of the brain. It has been suggested that accurate quantification of the relative contribution of heritable genetic and epigenetic variation is essential for understanding phenotypic divergence and adaptation in changing environments, a process requiring stable modulation of gene expression. The main challenge for epigenetics in psychology and psychiatry is to determine how experiences and environmental cues, including the nature of our nurture, influence the expression of neuronal genes to produce long-term individual differences in behavior, cognition, personality, and mental health. To this end, focusing on DNA and histone modifications and their initiators, mediators and readers may provide new inroads for understanding the molecular basis of phenotypic plasticity and disorders of the brain. In this chapter, we review recent discoveries highlighting epigenetic aspects of normal brain development and mental illness, as well as discuss some future directions in the field of behavioral epigenetics.
    Advances in genetics 08/2014; 86C:277-307. DOI:10.1016/B978-0-12-800222-3.00011-5 · 6.76 Impact Factor
  • Source
    • "In contrast, DNMT3a and 3b are believed to undergo transient de novo expression that induces CpG methylation in response to cellular stimuli (Okano et al., 1999). MBDs can recognize these newly methylated regions of DNA and are often associated with HDACs in MeCP1 and MeCP2 complexes, illustrating the potential for a direct link between DNA methylation and alterations in chromatin structure (Jones et al., 1998; Nan et al., 1998; Ng et al., 1999). Generally, hypermethylation of gene promoters occurs synchronously with histone deacetylation and decreased gene expression of many tumor suppressor genes (Baylin and Herman, 2000; Baylin et al., 2001; Stirzaker et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obligate intracellular pathogenic bacteria evolved to manipulate their host cells with a limited range of proteins constrained by their compact genomes. The harsh environment of a phagocytic defense cell is one that challenges the majority of commensal and pathogenic bacteria; yet, these are the obligatory vertebrate homes for important pathogenic species in the Anaplasmataceae family. Survival requires that the parasite fundamentally alter the native functions of the cell to allow its entry, intracellular replication, and transmission to a hematophagous arthropod. The small genomic repertoires encode several eukaryotic-like proteins, including ankyrin A (AnkA) of Anaplasma phagocytophilum and Ank200 and tandem-repeat containing proteins of Ehrlichia chaffeensis that localize to the host cell nucleus and directly bind DNA. As a model, A. phagocytophilum AnkA appears to directly alter host cell gene expression by recruiting chromatin modifying enzymes such as histone deacetylases and methyltransferases or by acting directly on transcription in cis. While cis binding could feasibly alter limited ranges of genes and cellular functions, the complex and dramatic alterations in transcription observed with infection are difficult to explain on the basis of individually targeted genes. We hypothesize that nucleomodulins can act broadly, even genome-wide, to affect entire chromosomal neighborhoods and topologically associating chromatin domains by recruiting chromatin remodeling complexes or by altering the folding patterns of chromatin that bring distant regulatory regions together to coordinate control of transcriptional reprogramming. This review focuses on the A. phagocytophilum nucleomodulin AnkA, how it impacts host cell transcriptional responses, and current investigations that seek to determine how these multifunctional eukaryotic-like proteins facilitate epigenetic alterations and cellular reprogramming at the chromosomal level.
    Frontiers in Genetics 08/2014; 5:274. DOI:10.3389/fgene.2014.00274
  • Source
    • "In fact, 40% of genes contain CpG-rich islands and up to 70% of all CpG dinucleotides in the genome are methylated [Bird, 2002; Wilson, 2008]. Methylated CpGs act as docking sites for methyl binding proteins which have the ability to oligomerize through the DNA in order to recruit chromatin remodeling complexes that, in turn, cause chromatin condensation and gene inactivation and silencing [Ng et al. 1999; Nikitina et al. 2007; Suzuki and Bird, 2008]. Non-CpG island methylation has also been reported to influence protein–DNA interactions , gene expression and chromatin structure and stability [Fouse et al. 2010]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is a worldwide epidemic of cardiovascular diseases causing not only a public health issue but also accounting for trillions of dollars of healthcare expenditure. Studies pertaining to epidemiology, pathophysiology, molecular biology, gene identification and genetic linkage maps have been able to lay a strong foundation for both the diagnosis and treatment of cardiovascular medicine. Although the concept of 'epigenetics' is not recent, the term in current usage is extended from the initial concept of 'controlling developmental gene expression and signaling pathways in undifferentiated zygotes' to include heritable changes to gene expression that are not from differences in the genetic code. The impact of epigenetics in cardiovascular disease is now emerging as an important regulatory key player at different levels from pathophysiology to therapeutics. This review focuses on the emerging role of epigenetics in major cardiovascular medicine specialties such as coronary artery disease, heart failure, cardiac hypertrophy and diabetes.
    Therapeutic Advances in Chronic Disease 07/2014; 5(4):178-87. DOI:10.1177/2040622314529325
Show more