The Molecular Basis of MeCP2 Function in the Brain

Meehan, 2017, Disease model discovery from 3,328 gene knockouts by the international mouse phenotyping Consortium, Nat. Genet., 49, 1231, 10.1038/ng.3901 2015, Large-scale discovery of novel genetic causes of developmental disorders, Nature, 519, 223, 10.1038/nature14135 Neul, 2010, Rett syndrome: revised diagnostic criteria and nomenclature, Ann, Neurol. Now., 68, 944 Kankirawatana, 2006, Early progressive encephalopathy in boys and MECP2 mutations, Neurology, 67, 164, 10.1212/01.wnl.0000223318.28938.45 Amir, 1999, Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2, Nat. Genet., 23, 185, 10.1038/13810 Hagberg, 1985, Rett's Syndrome: prevalence and impact on progressive severe mental retardation in girls, Acta Paediatr. Scand., 74, 405, 10.1111/j.1651-2227.1985.tb10993.x Kerr, 1985, Clinical topics Rett's syndrome in the west of Scotland, Br. Med. J., 291, 579, 10.1136/bmj.291.6495.579 Percy, 2010, Rett syndrome diagnostic criteria: lessons from the natural history study, Ann. Neurol., 68, 951, 10.1002/ana.22154 Hagberg, 1983, A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases, Ann. Neurol., 14, 471, 10.1002/ana.410140412 Tarquinio, 2015, The changing face of survival in Rett syndrome and MECP2-related disorders, Pediatr. Neurol., 53, 402, 10.1016/j.pediatrneurol.2015.06.003 Van Esch, 2011, MECP2 duplication syndrome, Mol. Syndromol., 2, 128, 10.1159/000329580 Van Esch, 2005, Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males, Am. J. Hum. Genet., 77, 442, 10.1086/444549 Guy, 2001, A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome, Nat. Genet., 27, 322, 10.1038/85899 Chen, 2001, Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice, Nat. Genet., 27, 327, 10.1038/85906 Brown, 2016, The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome, Hum. Mol. Genet., 25, 558, 10.1093/hmg/ddv496 Collins, 2004, Mild overexpression of MeCP2 causes a progressive neurological disorder in mice, Hum. Mol. Genet., 13, 2679, 10.1093/hmg/ddh282 Luikenhuis, 2004, Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice, Proc. Natl. Acad. Sci. U. S. A., 101, 6033, 10.1073/pnas.0401626101 Cheval, 2012, Postnatal inactivation reveals enhanced requirement for MeCP2 at distinct age windows, Hum. Mol. Genet., 21, 3806, 10.1093/hmg/dds208 McGraw, 2011, Adult neural function requires MeCP2, Science, 333, 186, 10.1126/science.1206593 Guy, 2007, Reversal of neurological defects in a mouse model of Rett syndrome, Science, 315, 1143, 10.1126/science.1138389 Robinson, 2012, Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome, Brain, 135, 2699, 10.1093/brain/aws096 Sztainberg, 2015, Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides, Nature, 528, 123, 10.1038/nature16159 Lewis, 1992, Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA, Cell, 69, 905, 10.1016/0092-8674(92)90610-O Nan, 1993, Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2, Nucleic Acids Res., 21, 4886, 10.1093/nar/21.21.4886 Cross, 1997, A component of the transcriptional repressor MeCP1 shares a motif with DNA methyltransferase and HRX proteins, Nat. Genet., 16, 256, 10.1038/ng0797-256 Hendrich, 1998, Identification and characterization of a family of mammalian methyl-CpG binding proteins, Mol. Cell. Biol., 18, 6538, 10.1128/MCB.18.11.6538 Strohner, 2001, NoRC - a novel member of mammalian ISWI-containing chromatin remodeling machines, EMBO J., 20, 4892, 10.1093/emboj/20.17.4892 Mabuchi, 2001, Novel candidate genes for leukemogenesis at chromosome 13q14 , a region commonly deleted in B-cell chronic lymphocytic leukemia deleted in B-cell chronic lymphocytic leukemia 1, Cancer Res., 61, 2870 Schultz, 2002, SETDB1: a novel KAP - 1 - associated histone H3 , lysine 9 - specific methyltransferase that contributes to HP1 - mediated silencing of euchromatic genes by KRAB zinc - finger proteins, Genes Dev., 16, 919, 10.1101/gad.973302 Roloff, 2003, Comparative study of methyl-CpG-binding domain proteins, BMC Genomics, 4, 1, 10.1186/1471-2164-4-1 Hendrich, 2003, The methyl-CpG binding domain and the evolving role of DNA methylation in animals, Trends Genet., 19, 269, 10.1016/S0168-9525(03)00080-5 Du, 2015, Methyl-CpG-binding domain proteins: readers of the epigenome, Epigenomics, 7, 1051, 10.2217/epi.15.39 Laget, 2010, The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA, PLoS One, 5, 10.1371/journal.pone.0011982 Skene, 2010, Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state, Mol. Cell, 37, 457, 10.1016/j.molcel.2010.01.030 Shahbazian, 2002, Insight into Rett syndrome: MeCP2 levels display tissue-and cell-specific differences and correlate with neuronal maturation, Hum. Mol. Genet., 11, 115, 10.1093/hmg/11.2.115 Wood, 2016, Tagging methyl-CpG-binding domain proteins reveals different spatiotemporal expression and supports distinct functions, Epigenomics, 8, 455, 10.2217/epi-2015-0004 Hendrich, 1999, The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites, Nature, 401, 301, 10.1038/45843 Zhao, 2003, Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function, Proc. Natl. Acad. Sci. U. S. A., 100, 6777, 10.1073/pnas.1131928100 Allan, 2008, The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits, Hum. Mol. Genet., 17, 2047, 10.1093/hmg/ddn102 Hendrich, 2001, Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development, Genes Dev., 15, 710, 10.1101/gad.194101 Sansom, 2003, Deficiency of Mbd2 suppresses intestinal tumorigenesis, Nat. Genet., 34, 145, 10.1038/ng1155 Millar, 2002, Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice, Science, 297, 403, 10.1126/science.1073354 Wong, 2002, Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation, Proc. Natl. Acad. Sci. U. S. A., 99, 14937, 10.1073/pnas.232579299 Kriaucionis, 2004, The major form of MeCP2 has a novel N-terminus generated by alternative splicing, Nucleic Acids Res., 32, 1818, 10.1093/nar/gkh349 Mnatzakanian, 2004, A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome, Nat. Genet., 36, 339, 10.1038/ng1327 Kerr, 2012, Transgenic complementation of MeCP2 deficiency: phenotypic rescue of Mecp2-null mice by isoform-specific transgenes, Eur. J. Hum. Genet., 20, 69, 10.1038/ejhg.2011.145 Klein, 2007, Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA, Nat. Neurosci., 10, 1513, 10.1038/nn2010 Gennarino, 2015, NUDT21 -spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation, Elife, 4, 10.7554/eLife.10782 Rodrigues, 2016, MECP2 is post-transcriptionally regulated during human neurodevelopment by combinatorial action of RNA-binding proteins and miRNAs, Cell Rep., 17, 720, 10.1016/j.celrep.2016.09.049 Zhou, 2006, Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation, Neuron, 52, 255, 10.1016/j.neuron.2006.09.037 Tao, 2009, Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function, Proc. Natl. Acad. Sci. U. S. A., 106, 4882, 10.1073/pnas.0811648106 Ebert, 2013, Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR, Nature, 499, 341, 10.1038/nature12348 Lombardi, 2017, An RNA interference screen identifies druggable regulators of MeCP2 stability, Sci. Transl. Med., 9, 10.1126/scitranslmed.aaf7588 Sheikh, 2017, MeCP2 isoform N-terminal modifications affect its degradation rate and are disrupted by the Ala2Val Rett mutation, Hum. Mol. Genet., 26, 4132, 10.1093/hmg/ddx300 Guy, 2011, The role of MeCP2 in the brain, Annu. Rev. Cell Dev. Biol., 27, 631, 10.1146/annurev-cellbio-092910-154121 Ross, 2016, Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes, Hum. Mol. Genet., 25, 4389 Valinluck, 2004, Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2), Nucleic Acids Res., 32, 4100, 10.1093/nar/gkh739 Mellén, 2012, MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system, Cell, 151, 1417, 10.1016/j.cell.2012.11.022 Hashimoto, 2012, Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation, Nucleic Acids Res., 40, 4841, 10.1093/nar/gks155 Sperlazza, 2017, Structural basis of MeCP2 distribution on non-CpG methylated and hydroxymethylated DNA, J. Mol. Biol., 429, 1581, 10.1016/j.jmb.2017.04.009 Nan, 1996, DNA methylation specifies chromosomal localization of MeCP2, Mol. Cell. Biol., 16, 414, 10.1128/MCB.16.1.414 Kudo, 2003, Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain, J. Med. Genet., 40, 487, 10.1136/jmg.40.7.487 Marchi, 2007, Spatio-temporal dynamics and localization of MeCP2 and pathological mutants in living cells, Epigenetics, 2, 187, 10.4161/epi.2.3.5057 Kumar, 2008, Analysis of protein domains and Rett syndrome mutations indicate that multiple regions influence chromatin-binding dynamics of the chromatin-associated protein MECP2 in vivo, J. Cell Sci., 121, 1128, 10.1242/jcs.016865 Schmiedeberg, 2009, A temporal threshold for formaldehyde crosslinking and fixation, PLoS One, 4, 10.1371/journal.pone.0004636 Bird, 1985, A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA, Cell, 40, 91, 10.1016/0092-8674(85)90312-5 Bird, 2002, DNA methylation patterns and epigenetic memory, Genes Dev., 16, 6, 10.1101/gad.947102 Deaton, 2011, CpG islands and the regulation of transcription, Genes Dev., 25, 1010, 10.1101/gad.2037511 Kinde, 2016, DNA methylation in the gene body influences MeCP2-mediated gene repression, Proc. Natl. Acad. Sci. U. S. A., 113, 15114, 10.1073/pnas.1618737114 Lagger, 2017, MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain, PLoS Genet., 13, 10.1371/journal.pgen.1006793 Gabel, 2015, Disruption of DNA-methylation-dependent long gene repression in Rett syndrome, Nature, 522, 89, 10.1038/nature14319 Cholewa-waclaw, 2019, Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic, Proc. Natl. Acad. Sci. U. S. A., 116, 14995, 10.1073/pnas.1903549116 Nikitina, 2007, MeCP2-Chromatin interactions include the formation of chromatosome-like structures and are altered in mutations causing Rett syndrome, J. Biol. Chem., 282, 28237, 10.1074/jbc.M704304200 Lister, 2013, Global epigenomic reconfiguration during mammalian brain development, Science, 341, 1237905, 10.1126/science.1237905 Varley, 2013, Dynamic DNA methylation across diverse human cell lines and tissues Dynamic DNA methylation across diverse human cell lines and tissues, Genome Res., 23, 555, 10.1101/gr.147942.112 Guo, 2014, Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain, Nat. Neurosci., 17, 215, 10.1038/nn.3607 Ramsahoye, 2000, Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a., Proc. Natl. Acad. Sci. U. S. A., 97, 5237, 10.1073/pnas.97.10.5237 Mo, 2015, Epigenomic signatures of neuronal diversity in the mammalian brain, Neuron, 86, 1369, 10.1016/j.neuron.2015.05.018 Renthal, 2018, Characterization of human mosaic Rett syndrome brain tissue by single-nucleus RNA sequencing, Nat. Neurosci., 21, 10.1038/s41593-018-0270-6 Stroud, 2017, Early-life gene expression in neurons modulates lasting epigenetic states, Cell, 171, 1151, 10.1016/j.cell.2017.09.047 Globisch, 2010, Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates, PLoS One, 5, 10.1371/journal.pone.0015367 Kriaucionis, 2014, The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain, Science, 325, 929 Ho, 2008, MeCP2 binding to DNA depends upon hydration at methyl-CpG, Mol. Cell, 29, 525, 10.1016/j.molcel.2007.12.028 Lei, 2019, Plasticity at the DNA recognition site of the MeCP2 mCG-binding domain, Biochim. Biophys. Acta - Gene Regul. Mech., 1862, 194409, 10.1016/j.bbagrm.2019.194409 Ghosh, 2010, Unique physical properties and interactions of the domains of methylated DNA binding protein 2 (MeCP2), Biochemistry, 49, 4395, 10.1021/bi9019753 Goffin, 2012, Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses, Nat. Neurosci., 15, 274, 10.1038/nn.2997 Johnson, 2017, Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome, Nat. Med., 23, 1203, 10.1038/nm.4406 Gandaglia, 2018, A novel Mecp2Y120D knock-in model displays similar behavioral traits but distinct molecular features compared to the Mecp2-null mouse implying precision medicine for the treatment of Rett syndrome, Mol. Neurobiol., 56, 4838, 10.1007/s12035-018-1412-2 Kucukkal, 2015, Impact of Rett syndrome mutations on MeCP2 MBD stability, Biochemistry, 54, 6357, 10.1021/acs.biochem.5b00790 Yang, 2016, Binding analysis of methyl-CpG binding domain of MeCP2 and Rett syndrome mutations, ACS Chem. Biol., 11, 2706, 10.1021/acschembio.6b00450 Kerr, 2008, Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice, Hum. Mol. Genet., 17, 1707, 10.1093/hmg/ddn061 Samaco, 2008, A partial loss of function allele of Methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome, Hum. Mol. Genet., 17, 1718, 10.1093/hmg/ddn062 Lamonica, 2017, Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome-like phenotypes, J. Clin. Investig., 127, 1889, 10.1172/JCI90967 V Koerner, 2018, Toxicity of overexpressed MeCP2 is independent of HDAC3 activity, Genes Dev., 32, 1514, 10.1101/gad.320325.118 Heckman, 2014, Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice, Elife, 10.7554/eLife.02676.011 Cuddapah, 2014, Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome, J. Med. Genet., 51, 152, 10.1136/jmedgenet-2013-102113 Stefanelli, 2016, Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association, Sci. Rep., 6, 28295, 10.1038/srep28295 Li, 2011, Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory, Nat. Neurosci., 14, 1001, 10.1038/nn.2866 Cohen, 2011, Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function, Neuron, 72, 72, 10.1016/j.neuron.2011.08.022 Della Ragione, 2016, MECP2 , a multi-talented modulator of chromatin architecture, Brief. Funct. Genom., 15, 420 Lyst, 2015, Rett syndrome: a complex disorder with simple roots, Nat. Rev. Genet., 16, 261, 10.1038/nrg3897 Nan, 1997, MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin, Cell, 88, 471, 10.1016/S0092-8674(00)81887-5 Nan, 1998, Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex, Nature, 393, 386, 10.1038/30764 Tudor, 2002, Nonlinear partial differential equations and applications: transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain, Proc. Natl. Acad. Sci. U. S. A., 99, 15536, 10.1073/pnas.242566899 Chahrour, 2008, MeCP2, a key contributor to neurological disease, activates and represses transcription, Science, 320, 1224, 10.1126/science.1153252 Kokura, 2001, The Ski protein family is required for MeCP2-mediated transcriptional repression, J. Biol. Chem., 276, 34115, 10.1074/jbc.M105747200 Lyst, 2013, Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor, Nat. Neurosci., 16, 898, 10.1038/nn.3434 Suzuki, 2003, Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression, Oncogene, 22, 8688, 10.1038/sj.onc.1207182 Mann, 2007, Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis, Cell Death Differ., 14, 275, 10.1038/sj.cdd.4401979 Forlani, 2010, The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis, Hum. Mol. Genet., 19, 3114, 10.1093/hmg/ddq214 Szulwach, 2010, Cross talk between microRNA and epigenetic regulation in adult neurogenesis, J. Cell Biol., 189, 127, 10.1083/jcb.200908151 Hwang, 2010, Up-regulation of the mu-opioid receptor gene is mediated through chromatin remodeling and transcriptional factors in differentiated neuronal cells, Mol. Pharmacol., 78, 58, 10.1124/mol.110.064311 Dhawan, 2011, Pancreatic beta cell identity is maintained by DNA methylation-mediated repression of Arx, Dev. Cell, 20, 419, 10.1016/j.devcel.2011.03.012 Subbanna, 2014, Ethanol induced acetylation of histone at G9a exon1 and G9a-mediated histone H3 dimethylation leads to neurodegeneration in neonatal mice, Neuroscience, 258, 422, 10.1016/j.neuroscience.2013.11.043 Xue, 2013, Holocarboxylase synthetase synergizes with methyl CpG binding protein 2 and DNA methyltransferase 1 in the transcriptional repression of long-terminal repeats, Epigenetics, 8, 504, 10.4161/epi.24449 Harikrishnan, 2005, Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing, Nat. Genet., 37, 254, 10.1038/ng1516 Kaludov, 2000, MeCP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery, Nucleic Acids Res., 28, 1921, 10.1093/nar/28.9.1921 Makałowski, 1998, Evolutionary parameters of the transcribed mammalian genome : an analysis of 2,820 orthologous rodent and human sequences, Proc. Natl. Acad. Sci. U. S. A., 95, 9407, 10.1073/pnas.95.16.9407 Kruusvee, 2017, Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders, Proc. Natl. Acad. Sci. U. S. A., 114, E3243, 10.1073/pnas.1700731114 Guy, 2018, A mutation-led search for novel functional domains in MeCP2, Hum. Mol. Genet., 27, 2531, 10.1093/hmg/ddy159 Lyst, 2016, Sequence-specific DNA binding by AT-hook motifs in MeCP2, FEBS Lett., 590, 2927, 10.1002/1873-3468.12328 Xu, 2018, Disruption of AT-hook 1 domain in MeCP2 protein caused behavioral abnormality in mice, Biochim. Biophys. Acta (BBA) - Mol. Basis Dis., 1864, 347, 10.1016/j.bbadis.2017.10.022 Baker, 2013, An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders, Cell, 152, 984, 10.1016/j.cell.2013.01.038 Georgel, 2003, Chromatin compaction by human MeCP2. Assembly of novel secondary chromatin structures in the absence of DNA methylation, J. Biol. Chem., 278, 32181, 10.1074/jbc.M305308200 Linhoff, 2015, A high-resolution imaging approach to investigate chromatin architecture in complex tissues, Cell, 163, 246, 10.1016/j.cell.2015.09.002 Yazdani, 2012, Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons, Stem Cells, 30, 2128, 10.1002/stem.1180 Ito-Ishida, 2018, Genome-wide distribution of linker histone H1.0 is independent of MeCP2, Nat. Neurosci., 21, 794, 10.1038/s41593-018-0155-8 Baker, 2015, Karyopherin alpha 3 and karyopherin alpha 4 mediate nuclear import of methyl-CpG binding protein 2, J. Biol. Chem., 290, 22485, 10.1074/jbc.M115.658104 Lyst, 2018, Affinity for DNA contributes to NLS independent nuclear localization of MeCP2, Cell Rep., 24, 2213, 10.1016/j.celrep.2018.07.099 Tillotson, 2017, Radically truncated MeCP2 reverses Rett syndrome-like neurological defects, Nature, 550, 398, 10.1038/nature24058 Agarwal, 2007, MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation, Nucleic Acids Res., 35, 5402, 10.1093/nar/gkm599 Buschdorf, 2004, A WW domain binding region in methyl-CpG-binding protein MeCP2: impact on Rett syndrome, J. Mol. Med., 82, 135, 10.1007/s00109-003-0497-9 Young, 2005, Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2, Proc. Natl. Acad. Sci. U. S. A., 102, 17551, 10.1073/pnas.0507856102 Cheng, 2014, MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex, Dev. Cell, 28, 547, 10.1016/j.devcel.2014.01.032 Piccolo, 2019, Mecp2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions, BioRxiv Sheikh, 2018, MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro, Hum. Mutat., 39, 717, 10.1002/humu.23409 Nan, 2007, Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation, Proc. Natl. Acad. Sci. U. S. A., 104, 2709, 10.1073/pnas.0608056104 Neul, 2012, The relationship of Rett syndrome and MECP2 disorders to autism, Transl. Res., 14, 253 Jentarra, 2010, Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation, BMC Neurosci., 11, 10.1186/1471-2202-11-19 Ma, 2014, Electrophysiological phenotypes of MeCP2 A140V mutant mouse model, CNS Neurosci. Ther., 20, 420, 10.1111/cns.12229 Gibbons, 1995, Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome), Cell, 80, 837, 10.1016/0092-8674(95)90287-2 Agarwal, 2011, MeCP2 Rett mutations affect large scale chromatin organization, Hum. Mol. Genet., 20, 4187, 10.1093/hmg/ddr346 Chia, 2016, A/T run geometry of B-form DNA is independent of bound methyl- CpG binding domain , cytosine methylation and flanking sequence, Sci. Rep., 6, 31212, 10.1038/srep31210 Jepsen, 2000, Combinatorial roles of the nuclear receptor corepressor in transcription and development, Cell, 102, 753, 10.1016/S0092-8674(00)00064-7 Jepsen, 2007, SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron, Nature, 450, 415, 10.1038/nature06270 Bhaskara, 2008, Article deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control, Mol. Cell, 30, 61, 10.1016/j.molcel.2008.02.030 Guo, 2015, The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor γ requires G protein pathway suppressor 2, J. Biol. Chem., 290, 3666, 10.1074/jbc.M114.598797 Dickinson, 2016, High-throughput discovery of novel developmental phenotypes, Nature, 537, 508, 10.1038/nature19356 Oberoi, 2011, Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery, Nat. Struct. Mol. Biol., 18, 177, 10.1038/nsmb.1983 Bassi, 1999, X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats, Am. J. Hum. Genet., 64, 1604, 10.1086/302408 Spruijt, 2013, Dynamic readers for 5-(Hydroxy)methylcytosine and its oxidized derivatives, Cell, 152, 1146, 10.1016/j.cell.2013.02.004 Yan, 2005, Molecular analysis of TBL1Y, a Y-linked homologue of TBL1X related with X-linked late-onset sensorineural deafness, J. Hum. Genet., 50, 175, 10.1007/s10038-005-0237-9 Zaghlula, 2018, Current clinical evidence does not support a link between TBL1XR1 and Rett syndrome: description of one patient with Rett features and a novel mutation in TBL1XR1, and a review of TBL1XR1 phenotypes, Am. J. Med. Genet. Part A., 176, 1683, 10.1002/ajmg.a.38689 Heinen, 2016, A specific mutation in TBL1XR1 causes Pierpont syndrome, J. Med. Genet., 53, 330, 10.1136/jmedgenet-2015-103233 Bracaglia, 2009, Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis, EMBO Rep., 10, 1327, 10.1038/embor.2009.217 Tweedie-Cullen, 2009, Comprehensive mapping of post-translational modifications on synaptic, nuclear, and histone proteins in the adult mouse brain, J. Proteome Res., 8, 4966, 10.1021/pr9003739 Huttlin, 2010, A tissue-specific atlas of mouse protein phosphorylation and expression, Cell, 143, 1174, 10.1016/j.cell.2010.12.001 Gonzales, 2012, Phosphorylation of distinct sites in MeCP2 modifies cofactor associations and the dynamics of transcriptional regulation, Mol. Cell. Biol., 32, 2894, 10.1128/MCB.06728-11 Yasui, 2014, Mice with an isoform-ablating Mecp2exon 1 mutation recapitulate the neurologic deficits of Rett syndrome, Hum. Mol. Genet., 23, 2447, 10.1093/hmg/ddt640 Bergo, 2015, Methyl-CpG binding protein 2 (MeCP2) localizes at the centrosome and is required for proper mitotic spindle organization, J. Biol. Chem., 290, 3223, 10.1074/jbc.M114.608125 Cheng, 2014, SUMOylation of MeCP2 is essential for transcriptional repression and hippocampal synapse development, J. Neurochem., 128, 798, 10.1111/jnc.12523 Tai, 2016, MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome, Nat. Commun., 7, 10552, 10.1038/ncomms10552 Zocchi, 2012, SIRT1-mediated deacetylation of MeCP2 contributes to BDNF expression, Epigenetics, 7, 695, 10.4161/epi.20733 Guo, 2014, Immunoaffinity enrichment and mass spectrometry analysis of protein methylation, Technol. Innov. Resour., 13, 372 Wang, 2010, Enrichment and site mapping of O-linked N-acetylglucosamine by a combination of chemical/enzymatic tagging, photochemical cleavage, and electron transfer dissociation mass spectrometry, Mol. Cell. Proteom., 9, 153, 10.1074/mcp.M900268-MCP200 Becker, 2016, Poly(ADP-ribosyl)ation of methyl CpG binding domain protein 2 regulates chromatin structure, J. Biol. Chem., 291, 4873, 10.1074/jbc.M115.698357 Kernohan, 2010, ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain, Dev. Cell, 18, 191, 10.1016/j.devcel.2009.12.017 Guarda, 2009, Interaction between the inner nuclear membrane lamin B receptor and the heterochromatic methyl binding protein, MeCP2, Exp. Cell Res., 315, 1895, 10.1016/j.yexcr.2009.01.019 Kimura, 2003, Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1., J. Biol. Chem., 278, 4806, 10.1074/jbc.M209923200 Cartron, 2013, Identification of TET1 partners that control its DNA-demethylating function, Genes Cancer, 4, 235, 10.1177/1947601913489020 Murphy, 2011, Co-localization of the oncogenic transcription factor MYCN and the DNA methyl binding protein MeCP2 at genomic sites in neuroblastoma, PLoS One, 6, 10.1371/journal.pone.0021436 Long, 2011, A brain-derived MeCP2 complex supports a role for MeCP2 in RNA processing, Biosci. Rep., 31, 333, 10.1042/BSR20100124 Li, 2016, Misregulation of alternative splicing in a mouse model of Rett syndrome, PLoS Genet., 12, 10.1371/journal.pgen.1006129 Dastidar, 2012, Isoform-specific toxicity of Mecp2 in postmitotic neurons: suppression of neurotoxicity by FoxG1, J. Neurosci., 32, 2846, 10.1523/JNEUROSCI.5841-11.2012 Mari, 2005, CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome, Hum. Mol. Genet., 14, 1935, 10.1093/hmg/ddi198 Khoshnan, 2012, Elevated IKKalpha accelerates the differentiation of human neuronal progenitor cells and induces MeCP2-dependent BDNF expression, PLoS One, 7, 10.1371/journal.pone.0041794 McFarland, 2014, MeCP2: a novel huntingtin interactor, Hum. Mol. Genet., 23, 1036, 10.1093/hmg/ddt499 Becker, 2013, Direct homo- and hetero-interactions of MeCP2 and MBD2, PLoS One, 8 Chang, 2006, The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression, Neuron, 49, 341, 10.1016/j.neuron.2005.12.027 Pelka, 2006, Mecp2 deficiency is associated with learning and cognitive deficits and altered gene activity in the hippocampal region of mice, Brain, 129, 887, 10.1093/brain/awl022 Orefice, 2016, Peripheral mechanosensory neuron dysfunction underlies tactile and behavioral deficits in mouse models of ASDs, Cell, 166, 299, 10.1016/j.cell.2016.05.033 Lawson-Yuen, 2007, Ube3a mRNA and protein expression are not decreased in Mecp2R168X mutant mice, Brain Res., 1180, 1, 10.1016/j.brainres.2007.08.039 Schaevitz, 2013, MeCP2 R168X male and female mutant mice exhibit Rett-like behavioral deficits, Genes Brain Behav., 12, 732 Wegener, 2014, Characterization of the MeCP2R168X knockin mouse model for Rett syndrome, PLoS One, 9, 10.1371/journal.pone.0115444 Pitcher, 2015, Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene, Hum. Mol. Genet., 24, 2662, 10.1093/hmg/ddv030 Casas-Delucchi, 2012, Targeted manipulation of heterochromatin rescues MeCP2 Rett mutants and re-establishes higher order chromatin organization, Nucleic Acids Res., 40, 10.1093/nar/gks784 Ballestar, 2000, Effects of Rett syndrome mutations of the Methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA, Biochemistry, 39, 7100, 10.1021/bi0001271 Yusufzai, 2000, Functional consequences of Rett syndrome mutations on human MeCP2, Nucleic Acids Res., 28, 4172, 10.1093/nar/28.21.4172 Free, 2001, DNA recognition by the methyl-CpG binding domain of MeCP2, J. Biol. Chem., 276, 3353, 10.1074/jbc.M007224200 Kudo, 2001, Functional analyses of MeCP2 mutations associated with Rett syndrome using transient expression systems, Brain Dev., 23, 165, 10.1016/S0387-7604(01)00345-X Baubec, 2013, Methylation-dependent and -independent genomic targeting principles of the MBD protein family, Cell, 153, 480, 10.1016/j.cell.2013.03.011 Sinnamon, 2017, Site-directed RNA repair of endogenous Mecp2 RNA in neurons, Proc. Natl. Acad. Sci. U. S. A., 114, E9395, 10.1073/pnas.1715320114 D'Annessa, 2018, Tyr120Asp mutation alters domain flexibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: atomistic characterization of a Rett syndrome causing mutation, Biochim. Biophys. Acta Gen. Subj., 1862, 1180, 10.1016/j.bbagen.2018.02.005 Ghosh, 2008, Rett syndrome-causing mutations in human MeCP2 result in diverse structural changes that impact folding and DNA interactions, J. Biol. Chem., 283, 20523, 10.1074/jbc.M803021200 Roak, 2012, Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders, Science, 338, 1619, 10.1126/science.1227764 Roak, 2012, Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations, Nature, 485, 246, 10.1038/nature10989