MeCP2: the long trip from a chromatin protein to neurological disorders.

Since the discovery of its fundamental involvement in Rett syndrome, methyl CpG binding protein 2 (MeCP2) has been the focus of an exhaustive biochemical and functional characterization. It is now becoming apparent that the intrinsic highly disordered nature of MeCP2, which is amenable to a plethora of post-translational modifications (PTMs), allows it to recognize a large number of protein interacting partners, including histones. MeCP2 is highly abundant in the brain and it is an important component of neuronal chromatin; nevertheless, the organization and implications of its involvement in terms of DNA methylation binding dependence and effects on transcription are still not well understood. Recent results have shown that MeCP2 plays an important role in brain development, aging, and in neurological disorders.

[1]  Rodney C. Samaco,et al.  Complexities of Rett Syndrome and MeCP2 , 2011, The Journal of Neuroscience.

[2]  J. Zwiller,et al.  Cocaine represses protein phosphatase-1Cβ through DNA methylation and Methyl-CpG Binding Protein-2 recruitment in adult rat brain , 2013, Neuropharmacology.

[3]  H. G. Dunn,et al.  Rett Syndrome: Review of Biological Abnormalities , 2001, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[4]  A. Hannan,et al.  Wheel running and environmental enrichment differentially modify exon‐specific BDNF expression in the hippocampus of wild‐type and pre‐motor symptomatic male and female Huntington's disease mice , 2009, Hippocampus.

[5]  Scott J. Russo,et al.  Chromatin Remodeling Is a Key Mechanism Underlying Cocaine-Induced Plasticity in Striatum , 2005, Neuron.

[6]  Elizabeth Head,et al.  Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human down syndrome brains. , 2013, The Journal of Biological Chemistry.

[7]  S. Henikoff,et al.  Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks , 2008, Nature.

[8]  R. Ghosh,et al.  Binding of the Rett syndrome protein, MeCP2, to methylated and unmethylated DNA and chromatin , 2010, IUBMB life.

[9]  A. Roberts,et al.  MeCP2 regulates ethanol sensitivity and intake , 2014, Addiction biology.

[10]  J. Ausió,et al.  Syndromes of disordered chromatin remodeling , 2003, Clinical genetics.

[11]  A. West,et al.  Phosphorylation of MeCP2 at Ser421 Contributes to Chronic Antidepressant Action , 2012, The Journal of Neuroscience.

[12]  J. LaSalle,et al.  Elevated methyl-CpG-binding protein 2 expression is acquired during postnatal human brain development and is correlated with alternative polyadenylation , 2002, Journal of Molecular Medicine.

[13]  Peter A. Jones,et al.  Functional DNA demethylation is accompanied by chromatin accessibility , 2013, Nucleic acids research.

[14]  Skirmantas Kriaucionis,et al.  MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. , 2012, Cell.

[15]  C. Wahlestedt,et al.  Striatal microRNA controls cocaine intake through CREB signaling , 2010, Nature.

[16]  A. Guidotti,et al.  Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice , 2013, Neuropharmacology.

[17]  Peng Jin,et al.  5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging , 2011, Nature Neuroscience.

[18]  J. Ausió,et al.  Histone variants--the structure behind the function. , 2006, Briefings in functional genomics & proteomics.

[19]  A. Bird,et al.  Reversal of Neurological Defects in a Mouse Model of Rett Syndrome , 2007, Science.

[20]  J. Buschdorf,et al.  A WW domain binding region in methyl-CpG-binding protein MeCP2: impact on Rett syndrome , 2004, Journal of Molecular Medicine.

[21]  R. Blumenthal,et al.  Coordinated chromatin control: structural and functional linkage of DNA and histone methylation. , 2010, Biochemistry.

[22]  Esteban Ballestar,et al.  The affinity of different MBD proteins for a specific methylated locus depends on their intrinsic binding properties. , 2003, Nucleic acids research.

[23]  P. Wade.  Methyl CpG‐binding proteins and transcriptional repression * , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[24]  A. Bird,et al.  DNA methylation landscapes: provocative insights from epigenomics , 2008, Nature Reviews Genetics.

[25]  A. Bird,et al.  DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG. , 2005, Molecular cell.

[26]  S. Scherer,et al.  A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome , 2004, Nature Genetics.

[27]  A. Bird,et al.  Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. , 1992, Nucleic acids research.

[28]  G. Nuovo,et al.  Chromosome 21-derived MicroRNAs Provide an Etiological Basis for Aberrant Protein Expression in Human Down Syndrome Brains* , 2009, The Journal of Biological Chemistry.

[29]  F. Lienert,et al.  Methylation-Dependent and -Independent Genomic Targeting Principles of the MBD Protein Family , 2013, Cell.

[30]  Linda Jeffery,et al.  Components of the DNA Methylation System of Chromatin Control Are RNA-binding Proteins* , 2004, Journal of Biological Chemistry.

[31]  M. Esteller,et al.  Impaired in vivo binding of MeCP2 to chromatin in the absence of its DNA methyl-binding domain , 2013, Nucleic acids research.

[32]  F. Saudou,et al.  Modification of Mecp2 dosage alters axonal transport through the Huntingtin/Hap1 pathway , 2012, Neurobiology of Disease.

[33]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[34]  D. Coleman-Derr,et al.  DNA methylation, H2A.Z, and the regulation of constitutive expression. , 2012, Cold Spring Harbor symposia on quantitative biology.

[35]  Ying Zhu,et al.  SUMOylation of MeCP2 is essential for transcriptional repression and hippocampal synapse development , 2014, Journal of neurochemistry.

[36]  S. Henikoff,et al.  Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis. , 2010, Genome research.

[37]  Eric C. Griffith,et al.  Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation , 2006, Neuron.

[38]  Christopher J. Oldfield,et al.  Intrinsically disordered protein. , 2001, Journal of molecular graphics & modelling.

[39]  L. Wilkins.  The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome , 2009, Neurology.

[40]  Christian Rosenmund,et al.  MeCP2 Controls Excitatory Synaptic Strength by Regulating Glutamatergic Synapse Number , 2007, Neuron.

[41]  Up-Regulated Methyl CpG Binding Protein-2 in Intractable Temporal Lobe Epilepsy Patients and a Rat Model , 2012, Neurochemical Research.

[42]  S. Akbarian,et al.  Epigenetic mechanisms in neurological disease , 2012, Nature Medicine.

[43]  Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications , 2012, Human Genetics.

[44]  G. Jennings,et al.  The neuronal noradrenaline transporter, anxiety and cardiovascular disease , 2006, Journal of psychopharmacology.

[45]  Stephanie C Huelga,et al.  Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs , 2012, Nature Neuroscience.

[46]  V. Ramakrishnan,et al.  Crystal structure of globular domain of histone H5 and its implications for nucleosome binding , 1993, Nature.

[47]  M. Rastegar,et al.  Brain Region-Specific Expression of MeCP2 Isoforms Correlates with DNA Methylation within Mecp2 Regulatory Elements , 2014, PloS one.

[48]  S. Rogers,et al.  PEST sequences and regulation by proteolysis. , 1996, Trends in biochemical sciences.

[49]  A. Bird,et al.  MeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin , 1997, Cell.

[50]  H. Ehrenreich,et al.  Mild overexpression of Mecp2 in mice causes a higher susceptibility toward seizures. , 2013, The American journal of pathology.

[51]  Michael L. Gonzales,et al.  Phosphorylation of Distinct Sites in MeCP2 Modifies Cofactor Associations and the Dynamics of Transcriptional Regulation , 2012, Molecular and Cellular Biology.

[52]  P. Sassone-Corsi,et al.  SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression , 2012, Epigenetics.

[53]  V. Uversky.  Intrinsically Disordered Proteins , 2014 .

[54]  H. Zoghbi,et al.  Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. , 2002, Human molecular genetics.

[55]  Michael L. Gonzales,et al.  Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome. , 2014, Human molecular genetics.

[56]  S. Cobb,et al.  MeCP2 and Rett syndrome: reversibility and potential avenues for therapy. , 2011, The Biochemical journal.

[57]  W. Kaufmann,et al.  Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome , 2014, Journal of Medical Genetics.

[58]  En Li,et al.  A Novel Dnmt3a Isoform Produced from an Alternative Promoter Localizes to Euchromatin and Its Expression Correlates with Activede Novo Methylation* , 2002, The Journal of Biological Chemistry.

[59]  J. Raber,et al.  A role for glia in the progression of Rett’s syndrome , 2011, Nature.

[60]  G. Maina,et al.  Serum levels of brain-derived neurotrophic factor in drug-naïve obsessive-compulsive patients: a case-control study. , 2010, Journal of affective disorders.

[61]  E. Ballestar,et al.  Methyl-CpG-binding proteins. Targeting specific gene repression. , 2001, European journal of biochemistry.

[62]  J. Ausió,et al.  MeCP2 post‐translational regulation through PEST domains: two novel hypotheses , 2009, BioEssays : news and reviews in molecular, cellular and developmental biology.

[63]  Rachel A. Horowitz-Scherer,et al.  Chromatin Compaction by Human MeCP2 , 2003, Journal of Biological Chemistry.

[64]  Yong-Mahn Han,et al.  Differential inheritance modes of DNA methylation between euchromatic and heterochromatic DNA sequences in ageing fetal bovine fibroblasts , 2001, FEBS letters.

[65]  M. Fraga,et al.  A profile of methyl-CpG binding domain protein occupancy of hypermethylated promoter CpG islands of tumor suppressor genes in human cancer. , 2006, Cancer research.

[66]  Jan-Fang Cheng,et al.  Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome , 2005, Nature Genetics.

[67]  Tatiana Nikitina,et al.  MeCP2 Binds Cooperatively to Its Substrate and Competes with Histone H1 for Chromatin Binding Sites , 2010, Molecular and Cellular Biology.

[68]  S. Haggarty,et al.  An epigenetic blockade of cognitive functions in the neurodegenerating brain , 2012, Nature.

[69]  Harrison W. Gabel,et al.  Genome-Wide Activity-Dependent MeCP2 Phosphorylation Regulates Nervous System Development and Function , 2011, Neuron.

[70]  M. Tahiliani,et al.  MLL Partner TET1 5-Hydroxymethylcytosine in Mammalian DNA by Conversion of 5-Methylcytosine to , 2009 .

[71]  A. Guidotti,et al.  Reelin promoter hypermethylation in schizophrenia. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[72]  Valerie H Adams,et al.  Intrinsic Disorder and Autonomous Domain Function in the Multifunctional Nuclear Protein, MeCP2* , 2007, Journal of Biological Chemistry.

[73]  J. Hansen,et al.  Coil‐to‐helix transitions in intrinsically disordered methyl CpG binding protein 2 and its isolated domains , 2012, Protein science : a publication of the Protein Society.

[74]  A. Varshavsky,et al.  The N-end rule of selective protein turnover: mechanistic aspects and functional implications. , 1987, Biochemical Society transactions.

[75]  S. Akbarian.  The Neurobiology of Rett Syndrome , 2003, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[76]  Stephen T. C. Wong,et al.  MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription , 2008, Science.

[77]  M. C. Cardoso,et al.  Direct Homo- and Hetero-Interactions of MeCP2 and MBD2 , 2013, PloS one.

[78]  R. Jaenisch,et al.  Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function , 2009, Proceedings of the National Academy of Sciences.

[79]  Allen D. Delaney,et al.  Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters , 2010, Nature.

[80]  R. Ghosh,et al.  Multiple Modes of Interaction between the Methylated DNA Binding Protein MeCP2 and Chromatin , 2006, Molecular and Cellular Biology.

[81]  C. Kuenzle,et al.  The chromatin repeat length of brain cortex and cerebellar neurons changes concomitant with terminal differentiation. , 1982, The EMBO journal.

[82]  H. Firth,et al.  Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression , 2010, Human mutation.

[83]  I. Blümcke,et al.  The emerging role of DNA methylation in epileptogenesis , 2012, Epilepsia.

[84]  B. Gowen,et al.  MeCP2 binds to nucleosome free (linker DNA) regions and to H3K9/H3K27 methylated nucleosomes in the brain , 2011, Nucleic acids research.

[85]  Zhijun Zhang,et al.  Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls , 2012, Human Genetics.

[86]  Heike Brand,et al.  Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A , 2005, Oncogene.

[87]  A. Feinberg.  Phenotypic plasticity and the epigenetics of human disease , 2007, Nature.

[88]  Zhong-Wei Zhang,et al.  MeCP2 is required for normal development of GABAergic circuits in the thalamus. , 2010, Journal of neurophysiology.

[89]  Ashok Patowary,et al.  Proximity of H2A.Z containing nucleosome to the transcription start site influences gene expression levels in the mammalian liver and brain , 2012, Nucleic acids research.

[90]  Albert Jeltsch,et al.  Cyclical DNA methylation of a transcriptionally active promoter , 2008, Nature.

[91]  Angela D. Wilkins,et al.  An AT-Hook Domain in MeCP2 Determines the Clinical Course of Rett Syndrome and Related Disorders , 2013, Cell.

[92]  J. Lupski,et al.  The Behavioral Phenotype in MECP2 Duplication Syndrome: A Comparison With Idiopathic Autism , 2013, Autism research : official journal of the International Society for Autism Research.

[93]  Dipendra K. Aryal,et al.  Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin , 2012, Neuropsychopharmacology.

[94]  A. Bird,et al.  MeCP2 binding to DNA depends upon hydration at methyl-CpG. , 2008, Molecular cell.

[95]  D. van der Kooy,et al.  Ventral Tegmental Area BDNF Induces an Opiate-Dependent–Like Reward State in Naïve Rats , 2009, Science.

[96]  P N Barlow,et al.  The solution structure of the domain from MeCP2 that binds to methylated DNA. , 1999, Journal of molecular biology.

[97]  C. Fuke,et al.  Age Related Changes in 5‐methylcytosine Content in Human Peripheral Leukocytes and Placentas: an HPLC‐based Study , 2004, Annals of human genetics.

[98]  Jörg Gsponer,et al.  Intrinsically disordered proteins: regulation and disease. , 2011, Current opinion in structural biology.

[99]  Marni J. Falk,et al.  MEF2C Haploinsufficiency features consistent hyperkinesis, variable epilepsy, and has a role in dorsal and ventral neuronal developmental pathways , 2013, neurogenetics.

[100]  Jim Selfridge,et al.  The role of MeCP2 in the brain. , 2009, Annual review of cell and developmental biology.

[101]  Rodney C. Samaco,et al.  Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities , 2009, Proceedings of the National Academy of Sciences.

[102]  T. Kubota,et al.  A patient with classic Rett syndrome with a novel mutation in MECP2 exon 1 , 2006, Clinical genetics.

[103]  S. Teichmann,et al.  Tight Regulation of Unstructured Proteins: From Transcript Synthesis to Protein Degradation , 2008, Science.

[104]  S. Peters,et al.  The MECP2 duplication syndrome , 2010, American journal of medical genetics. Part A.

[105]  J. Ausió,et al.  MeCP2 preferentially binds to methylated linker DNA in the absence of the terminal tail of histone H3 and independently of histone acetylation , 2008, FEBS letters.

[106]  C. Perez-Iratxeta,et al.  miRNA-132 orchestrates chromatin remodeling and translational control of the circadian clock. , 2011, Human molecular genetics.

[107]  A. Bird,et al.  DNA methylation specifies chromosomal localization of MeCP2 , 1996, Molecular and cellular biology.

[108]  Patricia Tueting,et al.  Brain-Derived Neurotrophic Factor Epigenetic Modifications Associated with Schizophrenia-like Phenotype Induced by Prenatal Stress in Mice , 2015, Biological Psychiatry.

[109]  Hilmar Bading,et al.  Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities , 2012, Nature Neuroscience.

[110]  S. Robson,et al.  Nucleosome-Interacting Proteins Regulated by DNA and Histone Methylation , 2010, Cell.

[111]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[112]  E. Cattaneo,et al.  Role of brain-derived neurotrophic factor in Huntington's disease , 2007, Progress in Neurobiology.

[113]  M. Bieda,et al.  Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes , 2007, Proceedings of the National Academy of Sciences.

[114]  D. Sarkar,et al.  Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, DNA methylation, and proopiomelanocortin (POMC) gene expression in β-endorphin-producing POMC neurons of the hypothalamus. , 2013, Alcoholism, clinical and experimental research.

[115]  J. Karlseder,et al.  The great unravelling: chromatin as a modulator of the aging process. , 2012, Trends in biochemical sciences.

[116]  L. Gierasch,et al.  Unique physical properties and interactions of the domains of methylated DNA binding protein 2. , 2010, Biochemistry.

[117]  Esteban Ballestar,et al.  Methyl‐CpG binding proteins identify novel sites of epigenetic inactivation in human cancer , 2003, The EMBO journal.

[118]  Marcelo A Wood,et al.  The Role of Histone Acetylation in Cocaine-Induced Neural Plasticity and Behavior , 2013, Neuropsychopharmacology.

[119]  J. LaSalle,et al.  Evolving role of MeCP2 in Rett syndrome and autism. , 2009, Epigenomics.

[120]  R. Ghosh,et al.  MeCP2-Chromatin Interactions Include the Formation of Chromatosome-like Structures and Are Altered in Mutations Causing Rett Syndrome* , 2007, Journal of Biological Chemistry.

[121]  D. Bates,et al.  Neuronal nuclei and glial nuclei from mammalian cerebral cortex. Nucleosome repeat lengths, DNA contents and H1 contents. , 1984, European journal of biochemistry.

[122]  H. Zoghbi,et al.  Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. , 2004, Human molecular genetics.

[123]  Tomohiro Hayakawa,et al.  Maintenance of self‐renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b , 2006, Genes to cells : devoted to molecular & cellular mechanisms.

[124]  E. Kavalali,et al.  The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity , 2013, Neuropsychopharmacology.

[125]  Robert S. Illingworth,et al.  Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. , 2010, Molecular cell.

[126]  M. Fraga,et al.  The impact of MECP2 mutations in the expression patterns of Rett syndrome patients , 2004, Human Genetics.

[127]  Yogesh K. Dwivedi.  Brain-derived neurotrophic factor: role in depression and suicide , 2009, Neuropsychiatric disease and treatment.