MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system

doi:10.1186/1756-8935-6-S1-P52

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MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system

Journal Article•DOI•

MeCP2 binds to 5hmc enriched within active genes and accessible chromatin in the nervous system

Marian Mellén¹, Pinar Ayata¹, Scott Dewell², Skirmantas Kriaucionis³, Nathaniel Heintz¹ - Show less +1 more•Institutions (3)

Howard Hughes Medical Institute¹, Rockefeller University², Ludwig Institute for Cancer Research³

18 Mar 2013-Epigenetics & Chromatin (BioMed Central)-Vol. 6, Iss: 1, pp 52

TL;DR: In this paper, a quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo is presented.

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Abstract: SUMMARY The high level of 5-hydroxymethylcytosine (5hmC) present in neuronal genomes suggests that mechanisms interpreting 5hmC in the CNS may differ from those present in embryonic stem cells. Here, we present quantitative, genome-wide analysis of 5hmC, 5-methylcytosine (5mC), and gene expression in differentiated CNS cell types in vivo. We report that 5hmC is enriched in active genes and that, surprisingly, strong depletion of 5mC is observed over these regions. The contribution of these epigenetic marks to gene expression depends critically on cell type. We identify methyl-CpG-binding protein 2 (MeCP2) as the major 5hmC-binding protein in the brain and demonstrate that MeCP2 binds 5hmC- and 5mC-containing DNA with similar high affinities. The Rett-syndrome-causing mutation R133C preferentially inhibits 5hmC binding. These findings support a model in which 5hmC and MeCP2 constitute a cell-specific epigenetic mechanism for regulation of chromatin structure and gene expression.

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Journal Article•DOI•

Global Epigenomic Reconfiguration During Mammalian Brain Development

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Ryan Lister¹, Ryan Lister², Eran A. Mukamel¹, Joseph R. Nery¹, Mark A. Urich¹, Clare A. Puddifoot¹, Nicholas D. Johnson¹, Jacinta Lucero¹, Yun Huang³, Andrew J. Dwork⁴, Matthew D. Schultz¹, Matthew D. Schultz⁵, Miao Yu⁶, Julian Tonti-Filippini², Holger Heyn, Shijun Hu⁷, Joseph C. Wu⁷, Anjana Rao³, Manel Esteller⁸, Chuan He⁶, Fatemeh Haghighi⁴, Terrence J. Sejnowski¹, Terrence J. Sejnowski⁵, M. Margarita Behrens¹, Joseph R. Ecker¹ - Show less +21 more•Institutions (8)

Salk Institute for Biological Studies¹, University of Western Australia², La Jolla Institute for Allergy and Immunology³, Columbia University⁴, University of California, San Diego⁵, University of Chicago⁶, Stanford University⁷, Catalan Institution for Research and Advanced Studies⁸

09 Aug 2013-Science

TL;DR: The results extend the knowledge of the unique role of DNA methylation in brain development and function, and offer a new framework for testing the role of the epigenome in healthy function and in pathological disruptions of neural circuits.

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Abstract: DNA methylation is implicated in mammalian brain development and plasticity underlying learning and memory. We report the genome-wide composition, patterning, cell specificity, and dynamics of DNA methylation at single-base resolution in human and mouse frontal cortex throughout their lifespan. Widespread methylome reconfiguration occurs during fetal to young adult development, coincident with synaptogenesis. During this period, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. Moreover, we found an mCH signature that identifies genes escaping X-chromosome inactivation. Last, whole-genome single-base resolution 5-hydroxymethylcytosine (hmC) maps revealed that hmC marks fetal brain cell genomes at putative regulatory regions that are CG-demethylated and activated in the adult brain and that CG demethylation at these hmC-poised loci depends on Tet2 activity.

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1,629 citations

Cites background or result from "MeCP2 binds to 5hmc enriched within..."

...hmC accumulates during early postnatal brain development in mice (31, 32), becoming enriched in highly expressed genes (33)....
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...Overall, transcriptional activity is associated with intragenic hmCG enrichment, as reported (33), with in utero establishment of adult hmCG patterns for cell type–specific genes and loss of hmC enrichment associated with developmentally coupled transcriptional down-regulation....
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...These constitutively highly expressed genes enriched for neuronal function also show extensive intragenic mCH hypomethylation in neurons in contrast to glia (box 3), and they are enriched for hmCG (box 4) as previously described (32, 33)....
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...Our base-resolution analysis of hmC using TAB-Seq revealed that intragenic and global hmCG levels are largely equivalent between chromosomes, whereas hmCG/CG is 22% lower on the male ChrX, consistent with previous reports from enrichment based detection of hmC (32, 33) (Fig....
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Journal Article•DOI•

The brain reward circuitry in mood disorders

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Scott J. Russo¹, Eric J. Nestler¹•Institutions (1)

Icahn School of Medicine at Mount Sinai¹

01 Sep 2013-Nature Reviews Neuroscience

TL;DR: This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression, and discusses some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.

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Abstract: Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioural domains. A recent literature has identified important structural and functional alterations within the brain's reward circuitry--particularly in the ventral tegmental area-nucleus accumbens pathway--that are associated with symptoms such as anhedonia and aberrant reward-associated perception and memory. This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.

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1,365 citations

Journal Article•DOI•

TET enzymes, TDG and the dynamics of DNA demethylation

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Rahul M. Kohli¹, Yi Zhang•Institutions (1)

University of Pennsylvania¹

24 Oct 2013-Nature

TL;DR: Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.

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Abstract: DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.

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1,336 citations

Journal Article•DOI•

TET-mediated active DNA demethylation: mechanism, function and beyond

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Xiaoji Wu¹, Yi Zhang•Institutions (1)

Howard Hughes Medical Institute¹

30 May 2017-Nature Reviews Genetics

TL;DR: Recent advances in biochemical and structural studies have revealed mechanistic insights into how TET and TDG mediate active DNA demethylation and many regulatory mechanisms of this process have been identified.

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Abstract: A key mode of regulating DNA methylation is through active demethylation driven by TET-mediated oxidation of 5-methylcytosine (5mC). This Review discusses our latest understanding of the mechanisms and regulation of active DNA demethylation, and the roles of active demethylation (and the oxidized 5mC intermediates) in gene regulation, genome stability, development and disease.

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1,012 citations

Journal Article•DOI•

Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives

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Cornelia G. Spruijt, Felix Gnerlich¹, Arne H. Smits, Toni Pfaffeneder¹, Pascal W.T.C. Jansen, Christina Bauer¹, Martin Münzel¹, Mirko Wagner¹, Markus Müller¹, Fariha Khan², Fariha Khan³, H. Christian Eberl⁴, Anneloes Mensinga, Arie B. Brinkman⁵, Konstantin Lephikov⁶, Udo Müller¹, Jörn Walter⁶, Rolf Boelens³, Hugo van Ingen³, Heinrich Leonhardt¹, Thomas Carell¹, Michiel Vermeulen - Show less +18 more•Institutions (6)

Ludwig Maximilian University of Munich¹, Pir Mehr Ali Shah Arid Agriculture University², Utrecht University³, Max Planck Society⁴, Radboud University Nijmegen⁵, Saarland University⁶

28 Feb 2013-Cell

TL;DR: Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation.

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897 citations

Cites background from "MeCP2 binds to 5hmc enriched within..."

...…binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC. Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation....
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References

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Journal Article•DOI•

A Translational Profiling Approach for the Molecular Characterization of CNS Cell Types

[...]

Myriam Heiman¹, Anne Schaefer¹, Shiaoching Gong¹, Jayms D. Peterson², Michelle Day², Keri E. Ramsey³, Mayte Suárez-Fariñas¹, Cordelia Schwarz⁴, Dietrich A. Stephan³, D. James Surmeier², Paul Greengard¹, Nathaniel Heintz¹, Nathaniel Heintz⁴ - Show less +9 more•Institutions (4)

Rockefeller University¹, Northwestern University², Translational Genomics Research Institute³, Howard Hughes Medical Institute⁴

14 Nov 2008-Cell

TL;DR: This genetically targeted translating ribosome affinity purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations.

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1,050 citations

"MeCP2 binds to 5hmc enriched within..." refers methods in this paper

...TRAP-Seq RNA from translating polysomes was extracted as previously described (Heiman et al., 2008) (see Extended Experimental Procedures)....
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...We have previously employed the translating ribosome affinity purification (TRAP) method to determine that each of these cell types expresses a unique complement of cell-specific gene products (Doyle et al., 2008; Heiman et al., 2008)....
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...Analysis of the TRAP-seq data generally confirms the conclusion reached previously that each of these cell types is characterized by the enriched expression of a large set of genes (Figure 1C) (Doyle et al., 2008; Heiman et al., 2008)....
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Journal Article•DOI•

Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome

[...]

Miao Yu¹, Gary C. Hon², Keith E. Szulwach³, Chun-Xiao Song¹, Liang Zhang¹, Audrey Kim², Xuekun Li³, Qing Dai¹, Yin Shen², Beomseok Park⁴, Jung Hyun Min⁴, Peng Jin³, Bing Ren², Chuan He¹ - Show less +10 more•Institutions (4)

University of Chicago¹, University of California, San Diego², Emory University³, University of Illinois at Chicago⁴

08 Jun 2012-Cell

TL;DR: Application of Tet-assisted bisulfite sequencing to embryonic stem cells not only confirms widespread distribution of 5hmC in the mammalian genome but also reveals sequence bias and strand asymmetry at5hmC sites.

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973 citations

"MeCP2 binds to 5hmc enriched within..." refers background in this paper

...For example, 5hmC is present preferentially in specific classes of promoter and enhancer elements that regulate the pluripotent state in ES cells (Pastor et al., 2011; Yu et al., 2012; Booth et al., 2012), whereas in the brain it is enriched in gene bodies and depleted from transcription start sites (TSS) (Szulwach et al....
[...]
...…present preferentially in specific classes of promoter and enhancer elements that regulate the pluripotent state in ES cells (Pastor et al., 2011; Yu et al., 2012; Booth et al., 2012), whereas in the brain it is enriched in gene bodies and depleted from transcription start sites (TSS) (Szulwach…...
[...]

Journal Article•DOI•

Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine

[...]

Chun-Xiao Song¹, Keith E. Szulwach², Ye Fu¹, Qing Dai¹, Chengqi Yi¹, Xuekun Li², Yujing Li², Chih Hsin Chen³, Wen Zhang¹, Xing Jian¹, Jing Wang¹, Li Zhang³, Timothy J. Looney³, Baichen Zhang⁴, Lucy A. Godley¹, Leslie M. Hicks⁴, Bruce T. Lahn³, Peng Jin², Chuan He¹ - Show less +15 more•Institutions (4)

University of Chicago¹, Emory University², Howard Hughes Medical Institute³, Donald Danforth Plant Science Center⁴

01 Jan 2011-Nature Biotechnology

TL;DR: This method uses the T4 bacteriophage β-glucosyltransferase to transfer an engineered glucose moiety containing an azide group onto the hydroxyl group of 5-hmC, a recently identified epigenetic modification present in substantial amounts in certain mammalian cell types.

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Abstract: In contrast to 5-methylcytosine (5-mC), which has been studied extensively, little is known about 5-hydroxymethylcytosine (5-hmC), a recently identified epigenetic modification present in substantial amounts in certain mammalian cell types. Here we present a method for determining the genome-wide distribution of 5-hmC. We use the T4 bacteriophage β-glucosyltransferase to transfer an engineered glucose moiety containing an azide group onto the hydroxyl group of 5-hmC. The azide group can be chemically modified with biotin for detection, affinity enrichment and sequencing of 5-hmC-containing DNA fragments in mammalian genomes. Using this method, we demonstrate that 5-hmC is present in human cell lines beyond those previously recognized. We also find a gene expression level-dependent enrichment of intragenic 5-hmC in mouse cerebellum and an age-dependent acquisition of this modification in specific gene bodies linked to neurodegenerative disorders.

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940 citations

"MeCP2 binds to 5hmc enriched within..." refers background or methods or result in this paper

...Genome-wide enrichment of 5hmC containing DNA fragments was done using a selective chemical labeling strategy (Song et al., 2011); 5mC was enriched using methylated DNA immunoprecipitation (MeDIP) (Jin et al....
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...In general, the distribution of 5hmC across the genome in these cell types was consistent with previous studies of brain tissue (Figure S2B) (Song et al., 2011; Szulwach (A) Metagene profiles of 5hmC and 5mC....
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...…that loss of MeCP2 can lead to downregulation of expressed genes (Ben-Shachar et al., 2009; this study), and that 5hmC is enriched in the gene bodies of highly expressed genes (Song et al., 2011; this study) suggests that MeCP2 binding to 5hmC may also play a role in facilitating gene expression....
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...Genome-wide enrichment of 5hmC containing DNA fragments was done using a selective chemical labeling strategy (Song et al., 2011); 5mC was enriched using methylated DNA immunoprecipitation (MeDIP) (Jin et al., 2010; Weber et al., 2005) followed by sequencing using Illumina platform....
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...5hmC was pulled down as described (Song et al., 2011; see Extended Experimental Procedures)....
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Journal Article•DOI•

Quantitative Sequencing of 5-Methylcytosine and 5-Hydroxymethylcytosine at Single-Base Resolution

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Michael J. Booth¹, Miguel R. Branco¹, Miguel R. Branco², Gabriella Ficz², David Oxley², Felix Krueger², Wolf Reik¹, Wolf Reik², Shankar Balasubramanian¹ - Show less +5 more•Institutions (2)

University of Cambridge¹, Babraham Institute²

18 May 2012-Science

TL;DR: In this article, the first method for quantitative mapping of 5hmC in genomic DNA at single-nucleotide resolution was proposed. But the method was not applied to the case of mouse embryonic stem cells.

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Abstract: 5-Methylcytosine can be converted to 5-hydroxymethylcytosine (5hmC) in mammalian DNA by the ten-eleven translocation (TET) enzymes. We introduce oxidative bisulfite sequencing (oxBS-Seq), the first method for quantitative mapping of 5hmC in genomic DNA at single-nucleotide resolution. Selective chemical oxidation of 5hmC to 5-formylcytosine (5fC) enables bisulfite conversion of 5fC to uracil. We demonstrate the utility of oxBS-Seq to map and quantify 5hmC at CpG islands (CGIs) in mouse embryonic stem (ES) cells and identify 800 5hmC-containing CGIs that have on average 3.3% hydroxymethylation. High levels of 5hmC were found in CGIs associated with transcriptional regulators and in long interspersed nuclear elements, suggesting that these regions might undergo epigenetic reprogramming in ES cells. Our results open new questions on 5hmC dynamics and sequence-specific targeting by TETs.

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882 citations

"MeCP2 binds to 5hmc enriched within..." refers background in this paper

...…in specific classes of promoter and enhancer elements that regulate the pluripotent state in ES cells (Pastor et al., 2011; Yu et al., 2012; Booth et al., 2012), whereas in the brain it is enriched in gene bodies and depleted from transcription start sites (TSS) (Szulwach et al., 2011)....
[...]
...For example, 5hmC is present preferentially in specific classes of promoter and enhancer elements that regulate the pluripotent state in ES cells (Pastor et al., 2011; Yu et al., 2012; Booth et al., 2012), whereas in the brain it is enriched in gene bodies and depleted from transcription start sites (TSS) (Szulwach et al....
[...]

Journal Article•DOI•

Application of a Translational Profiling Approach for the Comparative Analysis of CNS Cell Types

[...]

Joseph P. Doyle¹, Joseph D. Dougherty¹, Myriam Heiman², Eric F. Schmidt¹, Tanya R. Stevens¹, Guojun Ma¹, Sujata Bupp¹, Prerana Shrestha¹, Rajiv D. Shah¹, Martin L. Doughty², Shiaoching Gong², Shiaoching Gong¹, Paul Greengard², Nathaniel Heintz¹, Nathaniel Heintz² - Show less +11 more•Institutions (2)

Howard Hughes Medical Institute¹, Rockefeller University²

14 Nov 2008-Cell

TL;DR: In this article, translational profiles for 24 central nervous system (CNS) cell populations and identified known cell-specific and enriched transcripts for each population were presented. But, the translational profile for each cell population was not used in whole-tissue microarray studies.

...read moreread less

805 citations