{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T04:15:26Z","timestamp":1793333726129,"version":"4.5.0"},"reference-count":143,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>MeCP2 protein, encoded by the <jats:italic>MECP2<\/jats:italic> gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As <jats:italic>MECP2<\/jats:italic> gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with <jats:italic>Mecp2<\/jats:italic> gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (<jats:ext-link>https:\/\/pubmed.ncbi.nlm.nih.gov\/<\/jats:ext-link>) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.<\/jats:p>","DOI":"10.3389\/fgene.2021.624290","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T05:50:53Z","timestamp":1619157053000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":44,"title":["The Molecular Functions of MeCP2 in Rett Syndrome Pathology"],"prefix":"10.3389","volume":"12","author":[{"given":"Osman","family":"Sharifi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dag H.","family":"Yasui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15057","DOI":"10.1074\/jbc.M700855200","article-title":"Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2.","volume":"282","author":"Adams","year":"2007","journal-title":"J. Biol. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.cell.2018.12.035","article-title":"Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates.","volume":"176","author":"Alberti","year":"2019","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-017-0005-x","article-title":"Neural stem cells from a mouse model of Rett syndrome are prone to senescence, show reduced capacity to cope with genotoxic stress, and are impaired in the differentiation process.","volume":"50","author":"Alessio","year":"2018","journal-title":"Exper. Mol. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2.","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1016\/j.cell.2013.01.038","article-title":"An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders.","volume":"152","author":"Baker","year":"2013","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1038\/nn.2275","article-title":"Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology.","volume":"12","author":"Ballas","year":"2009","journal-title":"Nat. Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1016\/j.cell.2013.03.011","article-title":"Methylation-dependent and -independent genomic targeting principles of the mbd protein family.","volume":"153","author":"Baubec","year":"2013","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1093\/cercor\/bhv078","article-title":"Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms.","volume":"26","author":"Bedogni","year":"2016","journal-title":"Cereb. Cortex"},{"key":"B9","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.neuroscience.2014.02.043","article-title":"Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MECP2 T158A and R168X.","volume":"267","author":"Bissonnette","year":"2014","journal-title":"Neuroscience"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18020344","article-title":"Rett syndrome: a focus on gut microbiota.","volume":"18","author":"Borghi","year":"2017","journal-title":"Intern. J. Mol. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1093\/hmg\/ddh142","article-title":"X-chromosome inactivation ratios affect wild-type MeCP2 expression within mosaic Rett syndrome and Mecp2-\/+ mouse brain.","volume":"13","author":"Braunschweig","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1083\/jcb.200502062","article-title":"Methyl CpG-binding proteins induce large-scale chromatin reorganization during terminal differentiation.","volume":"169","author":"Brero","year":"2005","journal-title":"J. Cell Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3671","DOI":"10.1523\/JNEUROSCI.3735-16.2017","article-title":"CREB signaling is involved in rett syndrome pathogenesis.","volume":"37","author":"Bu","year":"2017","journal-title":"J. Neurosci."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-61030-1","article-title":"Complete profiling of Methyl-CpG-binding domains for combinations of cytosine modifications at CpG dinucleotides reveals differential read-out in normal and Rett-associated states.","volume":"10","author":"Buchmuller","year":"2020","journal-title":"Sci. Rep."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1038\/ng.2714","article-title":"A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome.","volume":"45","author":"Buchovecky","year":"2013","journal-title":"Nat. Genet."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1126\/science.1153252","article-title":"MeCP2, a key contributor to neurological disease, activates and represses transcription.","volume":"320","author":"Chahrour","year":"2008","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/nature09582","article-title":"Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes.","volume":"468","author":"Chao","year":"2010","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/85906","article-title":"Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice.","volume":"27","author":"Chen","year":"2001","journal-title":"Nat. Genet."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009087","article-title":"Quantitative analysis questions the role of MeCP2 as a global regulator of alternative splicing.","volume":"16","author":"Chhatbar","year":"2020","journal-title":"PLoS Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.molcel.2019.10.033","article-title":"MeCP2 represses enhancers through chromosome topology-associated DNA methylation.","volume":"77","author":"Clemens","year":"2020","journal-title":"Mol. Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2679","DOI":"10.1093\/hmg\/ddh282","article-title":"Mild overexpression of MeCP2 causes a progressive neurological disorder in mice.","volume":"13","author":"Collins","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3542","DOI":"10.1093\/nar\/gkaa102","article-title":"Absence of MeCP2 binding to non-methylated GT sequences in vivo.","volume":"48","author":"Connelly","year":"2020","journal-title":"Nucleic Acids Research"},{"key":"B23","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.conb.2019.07.002","article-title":"Genomic insights into MeCP2 function: a role for the maintenance of chromatin architecture.","volume":"59","author":"Connolly","year":"2019","journal-title":"Curr. Opin. Neurobiol."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0130183","article-title":"MeCP2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms.","volume":"10","author":"Conti","year":"2015","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1002\/ana.25797","article-title":"Comparison of core features in four developmental encephalopathies in the Rett natural history study.","volume":"88","author":"Cutri-French","year":"2020","journal-title":"Ann. Neurol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1097\/01.gim.0000250502.28516.3c","article-title":"Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.","volume":"8","author":"Del Gaudio","year":"2006","journal-title":"Genet. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1038\/nature10907","article-title":"Wild-type microglia arrest pathology in a mouse model of Rett syndrome.","volume":"484","author":"Derecki","year":"2012","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.nbd.2015.01.001","article-title":"MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells.","volume":"76","author":"Djuric","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.33417","article-title":"Mechanism and consequence of abnormal calcium homeostasis in rett syndrome astrocytes.","volume":"7","author":"Dong","year":"2018","journal-title":"eLife"},{"key":"B30","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1101\/gr.258400.119","article-title":"Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology.","volume":"30","author":"Enikanolaiye","year":"2020","journal-title":"Genome Res."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-020-0172-0","article-title":"Rett mutations attenuate phase separation of MeCP2.","volume":"6","author":"Fan","year":"2020","journal-title":"Cell Discov."},{"key":"B32","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/ejhg.2012.156","article-title":"The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy.","volume":"21","author":"Fehr","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"3353","DOI":"10.1074\/jbc.M007224200","article-title":"DNA Recognition by the Methyl-CpG binding domain of MeCP2.","volume":"276","author":"Free","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.neuron.2008.07.030","article-title":"Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress.","volume":"59","author":"Fyffe","year":"2008","journal-title":"Neuron"},{"key":"B35","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nature14319","article-title":"Disruption of DNA-methylation-dependent long gene repression in Rett syndrome.","volume":"522","author":"Gabel","year":"2015","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/mt.2012.200","article-title":"Improved survival and reduced phenotypic severity following AAV9\/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice.","volume":"21","author":"Gadalla","year":"2013","journal-title":"Mol. Therapy"},{"key":"B37","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.omtm.2017.04.007","article-title":"Development of a Novel AAV Gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome.","volume":"5","author":"Gadalla","year":"2017","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"13612","DOI":"10.1523\/JNEUROSCI.1854-13.2013","article-title":"Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome.","volume":"33","author":"Garg","year":"2013","journal-title":"J. Neurosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"32181","DOI":"10.1074\/jbc.M305308200","article-title":"Chromatin compaction by human MeCP2. Assembly of novel secondary chromatin structures in the absence of DNA methylation.","volume":"278","author":"Georgel","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"4395","DOI":"10.1021\/bi9019753","article-title":"Unique physical properties and interactions of the domains of methylated DNA binding protein 2.","volume":"49","author":"Ghosh","year":"2010","journal-title":"Biochemistry"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1073\/pnas.0610593104","article-title":"Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2.","volume":"104","author":"Giacometti","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B42","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1002\/ajmg.b.32015","article-title":"Mutations in MECP2 exon 1 in classical rett patients disrupt MECP2_e1 transcription, but not transcription of MECP2_e2.","author":"Gianakopoulos","year":"2012","journal-title":"Am. J. Med. Genet. Part B Neuropsychiatr. Genet."},{"key":"B43","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1038\/nn.2997","article-title":"Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses.","volume":"15","author":"Goffin","year":"2012","journal-title":"Nat. Neurosci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nn.3607","article-title":"Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain.","volume":"17","author":"Guo","year":"2014","journal-title":"Nat. Neurosci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1126\/science.1138389","article-title":"Reversal of neurological defects in a mouse model of Rett syndrome.","volume":"315","author":"Guy","year":"2007","journal-title":"Science"},{"key":"B46","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/85899","article-title":"A mouse Mecp2-null mutation causes neurological symptoms that mimic rett syndrome.","volume":"27","author":"Guy","year":"2001","journal-title":"Nat. Genet."},{"key":"B47","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/nature15694","article-title":"Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.","volume":"526","author":"Hao","year":"2015","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/ng1516","article-title":"Brahma links the SWI\/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing.","volume":"37","author":"Harikrishnan","year":"2005","journal-title":"Nat. Genet."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1126\/science.1210944","article-title":"Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA.","volume":"333","author":"He","year":"2011","journal-title":"Science"},{"key":"B50","doi-asserted-by":"publisher","first-page":"4983","DOI":"10.1093\/hmg\/ddw326","article-title":"Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis.","volume":"25","author":"Herrera","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"B51","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/ng1491","article-title":"Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome.","volume":"37","author":"Horike","year":"2005","journal-title":"Nat. Genet."},{"key":"B52","doi-asserted-by":"publisher","first-page":"13859","DOI":"10.1074\/jbc.M111.309864","article-title":"Methyl CpG-binding protein isoform MeCP2-e2 is dispensable for rett syndrome phenotypes but essential for embryo viability and placenta development.","volume":"287","author":"Itoh","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B53","doi-asserted-by":"publisher","first-page":"8746","DOI":"10.1523\/JNEUROSCI.1281-19.2020","article-title":"MeCP2 levels regulate the 3d structure of heterochromatic foci in mouse neurons.","volume":"40","author":"Ito-Ishida","year":"2020","journal-title":"J. Neurosci."},{"key":"B54","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/j.neuron.2015.10.029","article-title":"Loss of MeCP2 in Parvalbumin-and Somatostatin-expressing neurons in mice leads to distinct rett syndrome-like phenotypes.","volume":"88","author":"Ito-Ishida","year":"2015","journal-title":"Neuron"},{"key":"B55","doi-asserted-by":"publisher","first-page":"49479","DOI":"10.1074\/jbc.M409070200","article-title":"Components of the DNA methylation system of chromatin control are RNA-binding proteins.","volume":"279","author":"Jeffery","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1038\/nm.4406","article-title":"Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome.","volume":"23","author":"Johnson","year":"2017","journal-title":"Nat. Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/561","article-title":"Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.","volume":"19","author":"Jones","year":"1998","journal-title":"Nat. Genet."},{"key":"B58","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1002\/neu.10201","article-title":"The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells.","volume":"55","author":"Jung","year":"2003","journal-title":"J. Neurobiol."},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20153813","article-title":"Glial dysfunction in meCP2 deficiency models: implications for rett syndrome.","volume":"20","author":"Kahanovitch","year":"2019","journal-title":"Intern. J. Mol. Sci."},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2019.172796","article-title":"ANAVEX\u00ae 2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome.","volume":"187","author":"Kaufmann","year":"2019","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B61","doi-asserted-by":"publisher","first-page":"8356","DOI":"10.1093\/nar\/gku564","article-title":"Analysis of neonatal brain lacking ATRX or MeCP2 reveals changes in nucleosome density, CTCF binding and chromatin looping.","volume":"42","author":"Kernohan","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1093\/hmg\/ddn061","article-title":"Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice.","volume":"17","author":"Kerr","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1080\/15592294.2017.1391429","article-title":"MeCP2 interacts with chromosomal microRNAs in brain.","volume":"12","author":"Khan","year":"2017","journal-title":"Epigenetics"},{"key":"B64","doi-asserted-by":"publisher","first-page":"4596","DOI":"10.1073\/pnas.1311141111","article-title":"Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.","volume":"111","author":"Khwaja","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B65","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.expneurol.2009.12.007","article-title":"MeCP2 functions largely cell-autonomously, but also non-cell-autonomously, in neuronal maturation and dendritic arborization of cortical pyramidal neurons.","volume":"222","author":"Kishi","year":"2010","journal-title":"Exper. Neurol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.molcel.2005.07.021","article-title":"DNA binding selectivity of MeCP2 due to a requirement for A\/T sequences adjacent to methyl-CpG.","volume":"19","author":"Klose","year":"2005","journal-title":"Mol. Cell"},{"key":"B67","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1093\/nar\/gkh349","article-title":"The major form of MeCP2 has a novel N-terminus generated by alternative splicing.","volume":"32","author":"Kriaucionis","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"B68","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1126\/science.1169786","article-title":"The nuclear DNA base 5-hydroxymethylcytosine is present in purkinje neurons and the brain.","volume":"324","author":"Kriaucionis","year":"2009","journal-title":"Science"},{"key":"B69","doi-asserted-by":"publisher","first-page":"3029","DOI":"10.1093\/hmg\/ddw156","article-title":"MeCP2 co-ordinates liver lipid metabolism with the NCoR1\/HDAC3 corepressor complex.","volume":"25","author":"Kyle","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.170216","article-title":"Rett syndrome: a neurological disorder with metabolic components.","volume":"8","author":"Kyle","year":"2018","journal-title":"Open Biol."},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52981","article-title":"Losing dnmt3a dependent methylation in inhibitory neurons impairs neural function by a mechanism impacting rett syndrome.","volume":"9","author":"Lavery","year":"2020","journal-title":"eLife"},{"key":"B72","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.conb.2019.08.001","article-title":"The distinct methylation landscape of maturing neurons and its role in Rett syndrome pathogenesis.","volume":"59","author":"Lavery","year":"2019","journal-title":"Curr. Opin. Neurobiol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/0092-8674(92)90610-O","article-title":"Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA.","volume":"69","author":"Lewis","year":"1992","journal-title":"Cell"},{"key":"B74","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/s41586-020-2574-4","article-title":"MeCP2 links heterochromatin condensates and neurodevelopmental disease.","volume":"586","author":"Li","year":"2020","journal-title":"Nature"},{"key":"B75","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/nature10214","article-title":"A role for glia in the progression of Rett-syndrome.","volume":"475","author":"Lioy","year":"2011","journal-title":"Nature"},{"key":"B76","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nature08514","article-title":"Human DNA methylomes at base resolution show widespread epigenomic differences.","volume":"462","author":"Lister","year":"2009","journal-title":"Nature"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-020-00339-7","article-title":"DNA looping by two 5-methylcytosine-binding proteins quantified using nanofluidic devices.","volume":"13","author":"Liu","year":"2020","journal-title":"Epigenet. Chrom."},{"key":"B78","doi-asserted-by":"publisher","first-page":"7913","DOI":"10.1128\/mcb.21.23.7913-7922.2001","article-title":"Methylation-mediated proviral silencing is associated with MeCP2 recruitment and localized Histone H3 deacetylation.","volume":"21","author":"Lorincz","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"5346","DOI":"10.1523\/JNEUROSCI.5966-09.2010","article-title":"Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate.","volume":"30","author":"Maezawa","year":"2010","journal-title":"J. Neurosci."},{"key":"B80","doi-asserted-by":"publisher","first-page":"5051","DOI":"10.1523\/JNEUROSCI.0324-09.2009","article-title":"Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions.","volume":"29","author":"Maezawa","year":"2009","journal-title":"J. Neurosci."},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-019-0298-1","article-title":"MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2.","volume":"12","author":"Mart\u00ednez De Paz","year":"2019","journal-title":"Epigenet. Chrom."},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105235","article-title":"Severe offtarget effects following intravenous delivery of AAV9-MECP2 in a female mouse model of Rett syndrome.","volume":"149","author":"Matagne","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"B83","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.1038\/cr.2013.110","article-title":"Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition.","volume":"23","author":"Maunakea","year":"2013","journal-title":"Cell Res."},{"key":"B84","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.4161\/rna.26921","article-title":"Chromatin context and ncRNA highlight targets of MeCP2 in brain.","volume":"10","author":"Maxwell","year":"2013","journal-title":"RNA Bio."},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002982","article-title":"Rett syndrome: pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome.","volume":"3","author":"McCauley","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1126\/science.1206593","article-title":"Adult neural function requires MeCP2.","volume":"333","author":"McGraw","year":"2011","journal-title":"Science"},{"key":"B87","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.cell.2016.03.007","article-title":"TRIBE: hijacking an RNA-editing enzyme to identify cell-specific targets of RNA-binding proteins.","volume":"165","author":"McMahon","year":"2016","journal-title":"Cell"},{"key":"B88","doi-asserted-by":"publisher","first-page":"5085","DOI":"10.1093\/nar\/20.19.5085","article-title":"Characterization of MECP2, a vertebrate DNA binding protein with affinity for methylated DNA.","volume":"20","author":"Meehan","year":"1992","journal-title":"Nucleic Acids Res."},{"key":"B89","doi-asserted-by":"publisher","first-page":"3798","DOI":"10.1093\/hmg\/ddr298","article-title":"Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome.","volume":"20","author":"Meguro-Horike","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/j.cell.2012.11.022","article-title":"MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system.","volume":"151","author":"Mell\u00e9n","year":"2012","journal-title":"Cell"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1186\/s40348-016-0065-3","article-title":"Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome.","volume":"3","author":"Millar-B\u00fcchner","year":"2016","journal-title":"Mol. Cell. Pediatr."},{"key":"B92","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/ng1327","article-title":"A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome.","volume":"36","author":"Mnatzakanian","year":"2004","journal-title":"Nat. Genet."},{"key":"B93","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1038\/nature09544","article-title":"L1 retrotransposition in neurons is modulated by MeCP2.","volume":"468","author":"Muotri","year":"2010","journal-title":"Nature"},{"key":"B94","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/S0092-8674(00)81887-5","article-title":"MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin.","volume":"88","author":"Nan","year":"1997","journal-title":"Cell"},{"key":"B95","doi-asserted-by":"publisher","first-page":"28237","DOI":"10.1074\/jbc.M704304200","article-title":"MeCP2-chromatin interactions include the formation of chromatosome-like structures and are altered in mutations causing Rett syndrome.","volume":"282","author":"Nikitina","year":"2007","journal-title":"J. Biol. Chem."},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090645","article-title":"Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements.","volume":"9","author":"Olson","year":"2014","journal-title":"PLoS One"},{"key":"B97","doi-asserted-by":"publisher","first-page":"E5363","DOI":"10.1073\/pnas.1722546115","article-title":"Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome.","volume":"115","author":"Osenberg","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51449","article-title":"MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions.","volume":"8","author":"Piccolo","year":"2019","journal-title":"eLife"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.34031","article-title":"Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity.","volume":"7","author":"Pohodich","year":"2018","journal-title":"eLife"},{"key":"B100","doi-asserted-by":"publisher","first-page":"9044","DOI":"10.1093\/nar\/gky715","article-title":"Chromatin-dependent allosteric regulation of DNMT3A activity by MeCP2.","volume":"46","author":"Rajavelu","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05627-1","article-title":"Apparent bias toward long gene misregulation in MeCP2 syndromes disappears after controlling for baseline variations.","volume":"9","author":"Raman","year":"2018","journal-title":"Nat. Commun."},{"key":"B102","doi-asserted-by":"publisher","first-page":"3377","DOI":"10.1007\/s10803-015-2519-1","article-title":"Brief report: systematic review of Rett syndrome in males.","volume":"45","author":"Reichow","year":"2015","journal-title":"J. Autism Dev. Disord."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1038\/s41593-018-0270-6","article-title":"Characterization of human mosaic Rett syndrome brain tissue by single-nucleus RNA sequencing.","volume":"21","author":"Renthal","year":"2018","journal-title":"Nat. Neurosci."},{"key":"B104","doi-asserted-by":"publisher","first-page":"4389","DOI":"10.1093\/hmg\/ddw269","article-title":"Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes.","volume":"25","author":"Ross","year":"2016","journal-title":"Hum. Mole. Genet."},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11025","article-title":"Sequence features accurately predict genome-wide MeCP2 binding in vivo.","volume":"7","author":"Rube","year":"2016","journal-title":"Nat. Commun."},{"key":"B106","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1093\/hmg\/ddn062","article-title":"A partial loss of function allele of Methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome.","volume":"17","author":"Samaco","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B107","doi-asserted-by":"publisher","first-page":"21966","DOI":"10.1073\/pnas.0912257106","article-title":"Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities.","volume":"106","author":"Samaco","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B108","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1002\/ajmg.a.32776","article-title":"Novel exon 1 mutations in MECP2 implicate isoform MeCP2-e1 in classical rett syndrome.","volume":"149","author":"Saunders","year":"2009","journal-title":"Am. J. Med. Genet. Part A"},{"key":"B109","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1111\/gbb.12070","article-title":"MeCP2 R168X male and female mutant mice exhibit Rett-like behavioral deficits.","volume":"12","author":"Schaevitz","year":"2013","journal-title":"Genes Brain Behav."},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.15224","article-title":"Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression.","volume":"5","author":"Schafer","year":"2016","journal-title":"eLife"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.3390\/cells9040878","article-title":"MeCP2 and chromatin compartmentalization.","volume":"9","author":"Schmidt","year":"2020","journal-title":"Cells"},{"key":"B112","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/S0022-3476(94)70128-8","article-title":"Electrocardiographic findings in Rett syndrome: an explanation for sudden death?","volume":"125","author":"Sekul","year":"1994","journal-title":"J. Pediatr."},{"key":"B113","doi-asserted-by":"publisher","first-page":"E9395","DOI":"10.1073\/pnas.1715320114","article-title":"Site-directed RNA repair of endogenous Mecp2 RNA in neurons.","volume":"114","author":"Sinnamon","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107878","article-title":"In vivo repair of a protein underlying a neurological disorder by programmable RNA editing.","volume":"32","author":"Sinnamon","year":"2020","journal-title":"Cell Rep."},{"key":"B115","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.omtm.2017.04.006","article-title":"Improved MECP2 gene therapy extends the survival of MeCP2-null mice without apparent toxicity after intracisternal delivery.","volume":"5","author":"Sinnett","year":"2017","journal-title":"Mol. Therapy Methods Clin. Dev."},{"key":"B116","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.molcel.2010.01.030","article-title":"Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state.","volume":"37","author":"Skene","year":"2010","journal-title":"Mol. Cell"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-016-0185-y","article-title":"Altered gut microbiota in Rett syndrome.","volume":"4","author":"Strati","year":"2016","journal-title":"Microbiome"},{"key":"B118","doi-asserted-by":"publisher","first-page":"4888","DOI":"10.1093\/nar\/gkt213","article-title":"Impaired in vivo binding of MeCP2 to chromatin in the absence of its DNA methyl-binding domain.","volume":"41","author":"Stuss","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"B119","doi-asserted-by":"publisher","first-page":"12877","DOI":"10.1523\/JNEUROSCI.2674-14.2014","article-title":"Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes.","volume":"34","author":"Sugino","year":"2014","journal-title":"J. Neurosci."},{"key":"B120","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1097\/AJP.0b013e318274b6bd","article-title":"Parent-reported pain in Rett syndrome.","volume":"29","author":"Symons","year":"2013","journal-title":"Clin. J. Pain"},{"key":"B121","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1038\/nn.2959","article-title":"5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging.","volume":"14","author":"Szulwach","year":"2011","journal-title":"Nat. Neurosci."},{"key":"B122","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1126\/science.1170116","article-title":"Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.","volume":"324","author":"Tahiliani","year":"2009","journal-title":"Science"},{"key":"B123","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1086\/320109","article-title":"MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin.","volume":"68","author":"Trappe","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"B124","doi-asserted-by":"publisher","first-page":"3057","DOI":"10.1093\/nar\/gki612","article-title":"5-Halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl-CpG-binding domain of methyl-CpG-binding protein 2 (MeCP2).","volume":"33","author":"Valinluck","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"B125","doi-asserted-by":"publisher","first-page":"4100","DOI":"10.1093\/nar\/gkh739","article-title":"Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2).","volume":"32","author":"Valinluck","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw178","article-title":"Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome.","volume":"25","author":"Veeraragavan","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"B127","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1093\/hmg\/ddx087","article-title":"Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering.","volume":"26","author":"Vogel Ciernia","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"B128","doi-asserted-by":"publisher","first-page":"4077","DOI":"10.1093\/hmg\/ddy301","article-title":"MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome.","volume":"27","author":"Vogel Ciernia","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"B129","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1111\/nmo.12605","article-title":"MeCP2 in the enteric nervous system.","volume":"27","author":"Wahba","year":"2015","journal-title":"Neurogastroenterol. Motil."},{"key":"B130","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41422-020-0288-7","article-title":"Rett syndrome-causing mutations compromise MeCP2-mediated liquid-liquid phase separation of chromatin.","volume":"30","author":"Wang","year":"2020","journal-title":"Cell Res."},{"key":"B131","first-page":"1206","article-title":"Nuclear matrix - structure, function and pathogenesis.","volume":"70","author":"Wasag","year":"2016","journal-title":"Postepy Hog. Med. Dosw."},{"key":"B132","doi-asserted-by":"publisher","first-page":"5656","DOI":"10.1128\/mcb.17.9.5656","article-title":"Chicken MAR-binding protein ARBP is homologous to rat methyl-CpG-binding protein MeCP2.","volume":"17","author":"Weitzel","year":"1997","journal-title":"Mol. Cell. Biol."},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15134","article-title":"Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment.","volume":"8","author":"Wong","year":"2017","journal-title":"Nat. Commun."},{"key":"B134","doi-asserted-by":"publisher","first-page":"2447","DOI":"10.1093\/hmg\/ddt640","article-title":"Mice with an isoform-ablating Mecp2exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.","volume":"23","author":"Yasui","year":"2014","journal-title":"Hum. Mole. Genet."},{"key":"B135","doi-asserted-by":"publisher","first-page":"9416","DOI":"10.1073\/pnas.0707442104","article-title":"Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes.","volume":"104","author":"Yasui","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B136","doi-asserted-by":"publisher","first-page":"4311","DOI":"10.1093\/hmg\/ddr357","article-title":"15q11.2-13.3 chromatin analysis reveals epigenetic regulation of CHRNA7 with deficiencies in Rett and autism brain.","volume":"20","author":"Yasui","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"B137","doi-asserted-by":"publisher","first-page":"17551","DOI":"10.1073\/pnas.0507856102","article-title":"Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2.","volume":"102","author":"Young","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B138","doi-asserted-by":"publisher","first-page":"4493","DOI":"10.1093\/nar\/29.21.4493","article-title":"Methyl-CpG-binding protein 2 represses LINE-1 expression and retrotransposition but not Alu transcription.","volume":"29","author":"Yu","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049763","article-title":"Novel MeCP2 isoform-specific antibody reveals the endogenous MeCP2E1 expression in murine brain, primary neurons and Astrocytes.","volume":"7","author":"Zachariah","year":"2012","journal-title":"PLoS One"},{"key":"B140","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1080\/19491034.2017.1330238","article-title":"L1 retrotransposition is activated by Ten-eleven-translocation protein 1 and repressed by methyl-CpG binding proteins.","volume":"8","author":"Zhang","year":"2017","journal-title":"Nucleus"},{"key":"B141","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008043","article-title":"Somatic LINE-1 retrotransposition in cortical neurons and non-brain tissues of Rett patients and healthy individuals.","volume":"15","author":"Zhao","year":"2019","journal-title":"PLoS Genet."},{"key":"B142","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1177\/08830738050200090701","article-title":"MeCP2 dysfunction in humans and mice.","volume":"20","author":"Zoghbi","year":"2005","journal-title":"J. Child Neurol."},{"key":"B143","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9061669","article-title":"The anti-diabetic drug metformin rescues aberrant mitochondrial activity and restrains oxidative stress in a female mouse model of Rett syndrome.","volume":"9","author":"Zuliani","year":"2020","journal-title":"J. Clin. Med."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.624290\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T05:50:57Z","timestamp":1619157057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.624290\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,23]]},"references-count":143,"alternative-id":["10.3389\/fgene.2021.624290"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.624290","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,23]]},"article-number":"624290"}}