CFP1 Interacts with DNMT1 Independently of Association with the Setd1 Histone H3K4 Methyltransferase Complexes

Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States
DNA and cell biology (Impact Factor: 2.06). 09/2008; 27(10):533-43. DOI: 10.1089/dna.2007.0714
Source: PubMed


CXXC finger protein 1 (CFP1) is a component of the Setd1A and Setd1B methyltransferase complexes, localizes to euchromatic regions of the genome, and specifically binds unmethylated CpG dinucleotides in DNA. Murine embryos lacking CFP1 exhibit peri-implantation lethality, a developmental time that correlates with global epigenetic reprogramming. CFP1-deficient embryonic stem (ES) cells exhibit a 70% reduction in global cytosine methylation and a 60% decrease in maintenance DNA methyltransferase (DNMT1) activity. DNMT1 protein level is reduced 50% in CFP1-deficient ES cells. Experiments were performed to investigate the role of CFP1 in regulating maintenance cytosine methylation. Coimmunoprecipitation experiments reveal that endogenous DNMT1 and CFP1 interact in vivo. Protein regions required for the interaction between DNMT1 and CFP1 were mapped. Amino acids 169-493 and 970-1617 of DNMT1 are each sufficient for interaction with CFP1. Three regions spanning the CFP1 protein, amino acids 1-123, 103-367, and 361-656, are each sufficient for interaction with DNMT1. Interestingly, a single-point mutation (C375A) within CFP1 that abolishes the interaction with the Setd1A and Setd1B histone H3K4 methyltransferase complexes does not disrupt the interaction between CFP1 and DNMT1. This result indicates that CFP1 intersects the cytosine methylation machinery independently of its association with the Setd1 complexes.

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    • "Indeed, it is widely considered that the enrichment of CpGs at promoters is a vertebratespecific phenomenon that requires DNA methylation (Duncan and Miller 1980; Gardiner-Garden and Frommer 1987; Cooper and Krawczak 1989; Ehrlich et al. 1990; Antequera and Bird 1999; Caiafa and Zampieri 2005; Illingworth and Bird 2009; Turner et al. 2010; Deaton and Bird 2011). In mammals, nonmethylated CpGs are associated with active promoter chromatin features and bound by CXXC1 (CFP1), which is part of a SETD1A complex that catalyzes methylation of H3K4 (Lee and Skalnik 2005; Ansari et al. 2008; Butler et al. 2008; Tate et al. 2010; Thomson et al. 2010; Xu Ó 2014 Chen et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International ), as described at "
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    ABSTRACT: Most vertebrate promoters lie in unmethylated CpG-dense islands, while methylation of the more sparsely distributed CpGs in the remainder of the genome is thought to contribute to transcriptional repression. Non-methylated CG dinucleotides are recognized by CXXC finger protein 1 (CXXC1, also known as CFP1), which recruits SETD1A (also known as Set1) methyltransferase for trimethylation of histone H3 lysine 4, an active promoter mark. Genomic regions enriched for CpGs are thought to be either absent or irrelevant in invertebrates that lack DNA methylation, such as C. elegans, however, a CXXC1 ortholog (CFP-1) is present. Here we demonstrate that C. elegans CFP-1 targets promoters with high CpG density and that these promoters are marked by high levels of H3K4me3. Furthermore, as for mammalian promoters, high CpG content is associated with nucleosome depletion irrespective of transcriptional activity. We further show that highly occupied target (HOT) regions identified by the binding of a large number of transcription factors are CpG-rich promoters in C. elegans and human genomes, suggesting that the unusually high factor association at HOT regions may be a consequence of CpG-linked chromatin accessibility. Our results indicate that non-methylated CpG-dense sequence is a conserved genomic signal that promotes an open chromatin state, targeting by a CXXC1 ortholog and H3K4me3 modification in both C. elegans and human genomes.
    Full-text · Article · Mar 2014 · Genome Research
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    • "The crosstalk between histone modification and DNA methylation at the transcriptionally active and inactive regions is partly accomplished by a cfp1 (CXXC finger protein 1) and methyl-CpG binding proteins (MeCPs), respectively [22]. These proteins selectively bind to methylation-free and methylated CpG dinucleotides, respectively [22] [23] [24], encouraging recruitment of histone acetyltransferases and de-acetyltransferase and other epigenetic and non-epigenetic factors leading to regulation of transcription [23] [24]. Although the precise mechanisms of DNA de-methylation are not known, it has been suggested that DNA can also either passively or actively undergo de-methylation. "
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    ABSTRACT: Both genetic and epigenetic responses of organisms to environmental factors, including chemical exposures, influence adaptation, susceptibility to toxicity and biodiversity. In model organisms, it is established that epigenetic alterations, including changes to the methylome, can create a memory of the received signal. This is partly evidenced through the analysis of epigenetic differences that develop between identical twins throughout their lifetime. The epigenetic marks induce alterations to the gene expression profile, which, in addition to mediating homeostatic responses, have the potential to promote an abnormal physiology either immediately or at a later stage of development, for example leading to an adult onset of disease. Although this has been well established, epigenetic mechanisms are not considered in chemical risk assessment or utilised in the monitoring of the exposure and effects of chemicals and environmental change. In this review, epigenetic factors, specifically DNA methylation, are highlighted as mechanisms of adaptation and response to environmental factors and which, if persistent, have the potential, retrospectively, to reflect previous stress exposures. Thus, it is proposed that epigenetic "foot-printing" of organisms could identify classes of chemical contaminants to which they have been exposed throughout their lifetime. In some cases, the potential for persistent transgenerational modification of the epigenome may also inform on parental germ cell exposures. It is recommended that epigenetic mechanisms, alongside genetic mechanisms, should eventually be considered in environmental toxicity safety assessments and in biomonitoring studies. This will assist in determining the mode of action of toxicants, no observed adverse effect level and identification of biomarkers of toxicity for early detection and risk assessment in toxicology but there are critical areas that remain to be explored before this can be achieved.
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