Adrian Bird

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (95)1185.05 Total impact

  • Thomas Clouaire, Shaun Webb, Adrian Bird
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    ABSTRACT: Background Trimethylation of histone H3 lysine 4 (H3K4me3) accumulates at promoters in a gene activity dependent manner. The Set1 complex is responsible for most H3K4me3 in somatic cells and contains the conserved subunit Cfp1, which is implicated in targeting the Set1 complex to CpG islands in mammals. In mouse embryonic stem cells, Cfp1 is necessary for H3K4me3 accumulation at constitutively active gene promoters, but is not required to maintain steady-state transcription of the associated gene.ResultsHere we show that Cfp1 is instrumental for targeting H3K4me3 to promoters upon rapid transcriptional induction in response to external stimuli. Surprisingly, H3K4me3 accumulation is not required to ensure appropriate transcriptional output but rather plays gene specific roles. We also show that Cfp1-dependent H3K4me3 deposition contributes to H3K9 acetylation genome wide, suggesting that Cfp1 dependent H3K4me3 regulates overall H3K9 acetylation dynamics and is necessary for histone acetyl transferase recruitment. Finally, we observe increased antisense transcription at the start and end of genes that require Cfp1 for accurate deposition of H3K4me3 and H3K9ac.Conclusions Our results assign a key role for Cfp1 in establishing a complex active promoter chromatin state and shed light on how chromatin signaling pathways provide context-dependent transcriptional outcomes.
    Genome biology. 09/2014; 15(9):451.
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    ABSTRACT: Th1 and Th2 cell fates are traditionally viewed as mutually exclusive but recent work suggests that these lineages may be more plastic than previously thought. When isolating splenic CD4(+) T cells from mice infected with the parasitic helminth Schistosoma mansoni we observed a defined population of IFN-γ/IL-4 double-positive cells. These IFN-γ(+) IL-4(+) cells showed differences in DNA methylation at the Ifng and Il4 loci when compared with IFN-γ(+) IL-4(-) (Th1) and IFN-γ(-) IL-4(+) (Th2) cells, demonstrating that they represent a distinct effector cell population. IFN-γ(+) IL-4(+) cells also displayed a discrete DNA methylation pattern at a CpG island within the body of the Gata3 gene, which encodes the master regulator of Th2 identity. DNA methylation at this region correlated with decreased Gata3 levels, suggesting a possible role in controlling Gata3 expression. These data provide important insight into the molecular mechanisms behind co-existence of Th1 and Th2 characteristics. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 02/2014; · 4.97 Impact Factor
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    ABSTRACT: Methyl-CpG binding protein 2 (MECP2) is a protein that specifically binds methylated DNA, thus regulating transcription and chromatin organization. Mutations in the gene have been identified as the principal cause of Rett syndrome, a severe neurological disorder. Although the role of MECP2 has been extensively studied in nervous tissues, still very little is known about its function and cell type specific distribution in other tissues.
    Epigenetics & Chromatin 01/2014; 7:17. · 4.19 Impact Factor
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    ABSTRACT: Cell-specific gene expression is controlled by epigenetic modifications and transcription factor binding.While genome-wide maps for these protein-DNA interactions have become widely available,quantitative comparison of the resulting ChIP-Seq data sets remains challenging. Current approachesto detect differentially bound or modified regions are mainly borrowed from RNA-Seq data analysis,thus focusing on total counts of fragments mapped to a region, ignoring any information encoded inthe shape of the peaks. Here, we present MMDiff, a robust, broadly applicable method for detecting differences between sequencecount data sets. Based on quantifying shape changes in signal profiles, it overcomes challengesimposed by the highly structured nature of the data and the paucity of replicates.We first use a simulated data set to compare the performance of MMDiff with results obtained byfour alternative methods. We demonstrate that MMDiff excels when peak profiles change betweensamples. We next use MMDiff to re-analyse a recent data set of the histone modification H3K4me3elucidating the establishment of this prominent epigenomic marker. Our empirical analysis showsthat the method yields reproducible results across experiments, and is able to detect functional importantchanges in histone modifications. To further explore the broader applicability of MMDiff,we apply it to two ENCODE data sets: one investigating the histone modification H3K27ac and onemeasuring the genome-wide binding of the transcription factor CTCF. In both cases, MMDiff provesto be complementary to count-based methods. In addition, we can show that MMDiff is capable ofdirectly detecting changes of homotypic binding events at neighbouring binding sites. MMDiff isreadily available as a Bioconductor package. Our results demonstrate that higher order features of ChIP-Seq peaks carry relevant and often complementaryinformation to total counts, and hence are important in assessing differential histone modificationsand transcription factor binding. We have developed a new computational method, MMDiff,that is capable of exploring these features and therefore closes an existing gap in the analysis of ChIPSeqdata sets.
    BMC Genomics 11/2013; 14(1):826. · 4.40 Impact Factor
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    ABSTRACT: De novo mutations in the X-linked gene encoding the transcription factor methyl-CpG binding protein 2 (MECP2) are the most frequent cause of the neurological disorder Rett syndrome (RTT). Hemizygous males usually die of neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss of purposeful hand motions and speech, and motor abnormalities, which appear after a period of apparently normal development. Most studies have focused on male mouse models because of the shorter latency to and severity in symptoms, yet how well these mice mimic the disease in affected females is not clear. Very few therapeutic treatments have been proposed for females, the more gender-appropriate model. Here, we show that self-complementary AAV9, bearing MeCP2 cDNA under control of a fragment of its own promoter (scAAV9/MeCP2), is capable of significantly stabilizing or reversing symptoms when administered systemically into female RTT mice. To our knowledge, this is the first potential gene therapy for females afflicted with RTT.
    Journal of Neuroscience 08/2013; 33(34):13612-13620. · 6.91 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is an X-linked human neurodevelopmental disorder with features of autism and severe neurological dysfunction in females. RTT is caused by mutations in methyl-CpG-binding protein 2 (MECP2), a nuclear protein that in neurons regulates transcription, is expressed at high levels similar to that of histones, and binds to methylated cytosines broadly across the genome. By phosphotryptic mapping, we identify three sites (S86, S274 and T308) of activity-dependent MECP2 phosphorylation. Phosphorylation of these sites is differentially induced by neuronal activity, brain-derived neurotrophic factor, or agents that elevate the intracellular level of 3', 5'-cyclic AMP (cAMP), indicating that MECP2 may function as an epigenetic regulator of gene expression that integrates diverse signals from the environment. Here we show that the phosphorylation of T308 blocks the interaction of the repressor domain of MECP2 with the nuclear receptor co-repressor (NCoR) complex and suppresses the ability of MECP2 to repress transcription. In knock-in mice bearing the common human RTT missense mutation R306C, neuronal activity fails to induce MECP2 T308 phosphorylation, suggesting that the loss of T308 phosphorylation might contribute to RTT. Consistent with this possibility, the mutation of MECP2 T308A in mice leads to a decrease in the induction of a subset of activity-regulated genes and to RTT-like symptoms. These findings indicate that the activity-dependent phosphorylation of MECP2 at T308 regulates the interaction of MECP2 with the NCoR complex, and that RTT in humans may be due, in part, to the loss of activity-dependent MECP2 T308 phosphorylation and a disruption of the phosphorylation-regulated interaction of MECP2 with the NCoR complex.
    Nature 06/2013; 499(7458):341-345. · 38.60 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is a severe neurological disorder that is caused by mutations in the MECP2 gene. Many missense mutations causing RTT are clustered in the DNA-binding domain of MeCP2, suggesting that association with chromatin is critical for its function. We identified a second mutational cluster in a previously uncharacterized region of MeCP2. We found that RTT mutations in this region abolished the interaction between MeCP2 and the NCoR/SMRT co-repressor complexes. Mice bearing a common missense RTT mutation in this domain exhibited severe RTT-like phenotypes. Our data are compatible with the hypothesis that brain dysfunction in RTT is caused by a loss of the MeCP2 'bridge' between the NCoR/SMRT co-repressors and chromatin.
    Nature Neuroscience 06/2013; 16(7):898-902. · 15.25 Impact Factor
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    ABSTRACT: The discovery of gene body methylation, which refers to DNA methylation within gene coding region, suggests an as yet unknown role of DNA methylation at actively transcribed genes. In invertebrates, gene bodies are the primary targets of DNA methylation, and only a subset of expressed genes is modified. Here we investigate the tissue variability of both the global levels and distribution of 5-methylcytosine (5mC) in the sea squirt Ciona intestinalis. We find that global 5mC content of early developmental embryos is high, but is strikingly reduced in body wall tissues. We chose sperm and adult muscle cells, with high and reduced levels of global 5mC respectively, for genome-wide analysis of 5mC targets. By means of CXXC-affinity purification followed by deep sequencing (CAP-seq), and genome-wide bisulfite sequencing (BS-seq), we designated body-methylated and unmethylated genes in each tissue. Surprisingly, body-methylated and unmethylated gene groups are identical in the sperm and muscle cells. Our analysis of microarray expression data shows that gene body methylation is associated with broad expression throughout development. Moreover, transgenic analysis reveals contrasting gene body methylation at an identical gene-promoter combination when integrated at different genomic sites. We conclude that gene body methylation is not a direct regulator of tissue specific gene expression in C. intestinalis. Our findings reveal constant targeting of gene body methylation irrespective of cell type, and they emphasize a correlation between gene body methylation and ubiquitously expressed genes. Our transgenic experiments suggest that the promoter does not determine the methylation status of the associated gene body.
    Epigenetics & Chromatin 01/2013; 6(1):38. · 4.19 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal EEG and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. Mice in which Mecp2 expression was silenced (Mecp2(stop/y)) showed a higher seizure score (mean = 6 ± 0.8 compared to 4 ± 0.2 in wild-type, WT) and more rapid seizure onset (median onset = 10 mins in Mecp2(stop/y) and 32 mins in WT) when challenged with the convulsant drug kainic acid (25mg/Kg). Hippocampal slices from Mecp2(stop/y) brain displayed no spontaneous field potential activities under control conditions but showed higher power gamma frequency field potential oscillations compared to WT in response to kainic acid (400 nM) in vitro. Brain slices challenged with the GABA(A) receptor antagonist bicuculline (0.1-10μM) and the potassium channel blocker 4-aminopyridine (1-50μM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between MeCP2-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis.
    Neuroscience 12/2012; · 3.12 Impact Factor
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    ABSTRACT: Mutations in the gene encoding the methyl-CpG-binding protein MECP2 are the major cause of Rett syndrome, an autism spectrum disorder mainly affecting young females. MeCP2 is an abundant chromatin-associated protein, but how and when its absence begins to alter brain function is still far from clear. Using a stem cell-based system allowing the synchronous differentiation of neuronal progenitors, we found that in the absence of MeCP2, the size of neuronal nuclei fails to increase at normal rates during differentiation. This is accompanied by a marked decrease in the rate of ribonucleotide incorporation, indicating an early role of MeCP2 in regulating total gene transcription, not restricted to selected mRNAs. We also found that the levels of brain-derived neurotrophic factor (BDNF) were decreased in mutant neurons, while those of the presynaptic protein synaptophysin increased at similar rates in wild-type and mutant neurons. By contrast, nuclear size, transcription rates, and BDNF levels remained unchanged in astrocytes lacking MeCP2. Re-expressing MeCP2 in mutant neurons rescued the nuclear size phenotype as well as BDNF levels. These results reveal a new role of MeCP2 in regulating overall RNA synthesis in neurons during the course of their maturation, in line with recent findings indicating a reduced nucleolar size in neurons of the developing brain of mice lacking Mecp2. STEM Cells2012;30:2128-2139.
    Stem Cells 08/2012; 30(10):2128-39. · 7.70 Impact Factor
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    ABSTRACT: Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised promoters. The Set1 complex is responsible for most somatic H3K4me3 and contains the conserved subunit CxxC finger protein 1 (Cfp1), which binds to unmethylated CpGs and links H3K4me3 with CpG islands (CGIs). Here we report that Cfp1 plays unanticipated roles in organizing genome-wide H3K4me3 in embryonic stem cells. Cfp1 deficiency caused two contrasting phenotypes: drastic loss of H3K4me3 at expressed CGI-associated genes, with minimal consequences for transcription, and creation of "ectopic" H3K4me3 peaks at numerous regulatory regions. DNA binding by Cfp1 was dispensable for targeting H3K4me3 to active genes but was required to prevent ectopic H3K4me3 peaks. The presence of ectopic peaks at enhancers often coincided with increased expression of nearby genes. This suggests that CpG targeting prevents "leakage" of H3K4me3 to inappropriate chromatin compartments. Our results demonstrate that Cfp1 is a specificity factor that integrates multiple signals, including promoter CpG content and gene activity, to regulate genome-wide patterns of H3K4me3.
    Genes & development 08/2012; 26(15):1714-28. · 12.08 Impact Factor
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    ABSTRACT: Rett Syndrome is a neurological disorder caused by mutations in the X-linked MECP2 gene. Mouse models where Mecp2 is inactivated or mutated recapitulate several features of the disorder and have demonstrated a requirement for the protein to ensure brain function in adult mice. We deleted the Mecp2 gene in ~80% of brain cells at three postnatal ages to determine whether the need for MeCP2 varies with age. Inactivation at all three time points induced Rett-like phenotypes and caused premature death of the animals. We find two threshold ages beyond which the requirement for MeCP2 markedly increases in stringency. The earlier threshold (8-14 weeks), when inactivated mice develop symptoms, represents early adulthood in the mouse and coincides with the period when Mecp2-null mice exhibit terminal symptoms. Unexpectedly, we identified a later age threshold (30-45 weeks) beyond which an 80% reduction in MeCP2 is incompatible with life. This finding suggests an enhanced role for MeCP2 in the aging brain.
    Human Molecular Genetics 05/2012; 21(17):3806-14. · 7.69 Impact Factor
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    ABSTRACT: Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 display a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. Although routinely classified as a neurodevelopmental disorder, many aspects of the mouse phenotype can be effectively reversed by activation of a quiescent Mecp2 gene in adults. This suggests that absence of Mecp2 during brain development does not irreversibly compromise brain function. It is conceivable, however, that deep-seated neurological defects persist in mice rescued by late activation of Mecp2. To test this possibility, we have quantitatively analysed structural and functional plasticity of the rescued adult male mouse brain. Activation of Mecp2 in ∼70% of neurons reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. Restoration of Mecp2 expression was also accompanied by a significant improvement in respiratory and sensory-motor functions, including breathing pattern, grip strength, balance beam and rotarod performance. Our findings sustain the view that MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete.
    Brain 04/2012; 135(Pt 9):2699-710. · 9.92 Impact Factor
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    Adrian Bird
    Nature Genetics 11/2011; 43(11):1050-1. · 35.21 Impact Factor
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    ABSTRACT: Human and mouse genomes contain a similar number of CpG islands (CGIs), which are discrete CpG-rich DNA sequences associated with transcription start sites. In both species, ∼50% of all CGIs are remote from annotated promoters but, nevertheless, often have promoter-like features. To determine the role of CGI methylation in cell differentiation, we analyzed DNA methylation at a comprehensive CGI set in cells of the mouse hematopoietic lineage. Using a method that potentially detects ∼33% of genomic CpGs in the methylated state, we found that large differences in gene expression were accompanied by surprisingly few DNA methylation changes. There were, however, many DNA methylation differences between hematopoietic cells and a distantly related tissue, brain. Altered DNA methylation in the immune system occurred predominantly at CGIs within gene bodies, which have the properties of cell type-restricted promoters, but infrequently at annotated gene promoters or CGI flanking sequences (CGI "shores"). Unexpectedly, elevated intragenic CGI methylation correlated with silencing of the associated gene. Differentially methylated intragenic CGIs tended to lack H3K4me3 and associate with a transcriptionally repressive environment regardless of methylation state. Our results indicate that DNA methylation changes play a relatively minor role in the late stages of differentiation and suggest that intragenic CGIs represent regulatory sites of differential gene expression during the early stages of lineage specification.
    Genome Research 05/2011; 21(7):1074-86. · 14.40 Impact Factor
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    Aimée M Deaton, Adrian Bird
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    ABSTRACT: Vertebrate CpG islands (CGIs) are short interspersed DNA sequences that deviate significantly from the average genomic pattern by being GC-rich, CpG-rich, and predominantly nonmethylated. Most, perhaps all, CGIs are sites of transcription initiation, including thousands that are remote from currently annotated promoters. Shared DNA sequence features adapt CGIs for promoter function by destabilizing nucleosomes and attracting proteins that create a transcriptionally permissive chromatin state. Silencing of CGI promoters is achieved through dense CpG methylation or polycomb recruitment, again using their distinctive DNA sequence composition. CGIs are therefore generically equipped to influence local chromatin structure and simplify regulation of gene activity.
    Genes & development 05/2011; 25(10):1010-22. · 12.08 Impact Factor
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    ABSTRACT: Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes. Owing to its ability to excise thymine when mispaired with guanine, it was proposed to act against the mutability of 5-methylcytosine (5-mC) deamination in mammalian DNA. However, TDG was also found to interact with transcription factors, histone acetyltransferases and de novo DNA methyltransferases, and it has been associated with DNA demethylation in gene promoters following activation of transcription, altogether implicating an engagement in gene regulation rather than DNA repair. Here we use a mouse genetic approach to determine the biological function of this multifaceted DNA repair enzyme. We find that, unlike other DNA glycosylases, TDG is essential for embryonic development, and that this phenotype is associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg null embryos (mouse embryonic fibroblasts, MEFs) show impaired gene regulation, coincident with imbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells (ESCs), but epigenetic aberrations only appear upon cell lineage commitment. We show that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant de novo methylation. We thus conclude that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage committed cells.
    Nature 02/2011; 470(7334):419-23. · 38.60 Impact Factor
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    Adrian Bird
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    ABSTRACT: The operon model proposed the existence of a category of proteins that control gene expression by interacting with specific DNA sequences. Since then, a large number of transcription factors recognizing a diversity of sequence motifs have been discovered. This article discusses an unusually short protein recognition sequence, 5'CG, which is read by multiple DNA binding proteins. CG exists in three distinct chemical states, two of which bind mutually exclusively to proteins that modulate chromatin structure. Non-methylated CG, which is highly concentrated at CpG island promoters, recruits enzymes that create the mark of promoter activity, trimethyl-lysine 4 of histone H3. Methylated CG, on the other hand, is a gene silencing mark and accordingly recruits enzymes that deacetylate histones. Thus, CG, despite its simplicity, has the properties of a genome-wide signalling module that adds a layer of positive or negative control over gene expression.
    Journal of Molecular Biology 02/2011; 409(1):47-53. · 3.91 Impact Factor
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    ABSTRACT: Methyl-CpG binding protein 2 (MeCP2) was first identified in 1992 as a protein that binds specifically to methylated DNA. Mutations in the MECP2 gene were later found to be the cause of an autism spectrum disorder, Rett syndrome. Despite almost 20 years of research into the molecular mechanisms of MeCP2 function, many questions are yet to be answered conclusively. This review considers several key questions and attempts to evaluate the current state of evidence. For example, is MeCP2 just a methyl-CpG binding protein? Is it a multifunctional protein or primarily a transcriptional repressor? We also consider whether MeCP2, as a chromosome-binding protein, acts at specific sites within the genome or more globally, and in which cell types it is functionally important. Finally, we consider two alternative views of MeCP2 in the brain: as a regulator of brain development or as a factor that helps maintain neuronal/glial function.
    Annual Review of Cell and Developmental Biology 10/2010; 27:631-52. · 17.98 Impact Factor
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    ABSTRACT: CpG islands (CGIs) are prominent in the mammalian genome owing to their GC-rich base composition and high density of CpG dinucleotides. Most human gene promoters are embedded within CGIs that lack DNA methylation and coincide with sites of histone H3 lysine 4 trimethylation (H3K4me3), irrespective of transcriptional activity. In spite of these intriguing correlations, the functional significance of non-methylated CGI sequences with respect to chromatin structure and transcription is unknown. By performing a search for proteins that are common to all CGIs, here we show high enrichment for Cfp1, which selectively binds to non-methylated CpGs in vitro. Chromatin immunoprecipitation of a mono-allelically methylated CGI confirmed that Cfp1 specifically associates with non-methylated CpG sites in vivo. High throughput sequencing of Cfp1-bound chromatin identified a notable concordance with non-methylated CGIs and sites of H3K4me3 in the mouse brain. Levels of H3K4me3 at CGIs were markedly reduced in Cfp1-depleted cells, consistent with the finding that Cfp1 associates with the H3K4 methyltransferase Setd1 (refs 7, 8). To test whether non-methylated CpG-dense sequences are sufficient to establish domains of H3K4me3, we analysed artificial CpG clusters that were integrated into the mouse genome. Despite the absence of promoters, the insertions recruited Cfp1 and created new peaks of H3K4me3. The data indicate that a primary function of non-methylated CGIs is to genetically influence the local chromatin modification state by interaction with Cfp1 and perhaps other CpG-binding proteins.
    Nature 04/2010; 464(7291):1082-6. · 38.60 Impact Factor

Publication Stats

11k Citations
1,185.05 Total Impact Points

Institutions

  • 1992–2014
    • The University of Edinburgh
      • • Wellcome Trust Centre for Cell Biology
      • • Institute of Cell Biology
      Edinburgh, Scotland, United Kingdom
  • 2010
    • University of Glasgow
      • Institute of Neuroscience and Psychology
      Glasgow, SCT, United Kingdom
  • 2007
    • Cardiff University
      • School of Biosciences
      Cardiff, Wales, United Kingdom
  • 2005
    • Max Planck Institute for Molecular Genetics
      • Department of Human Molecular Genetics
      Berlín, Berlin, Germany
  • 1989–1992
    • Research Institute of Molecular Pathology
      Wien, Vienna, Austria
  • 1988–1992
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom