The Molecular Functions of MeCP2 in Rett Syndrome Pathology

Overview

Journal Front Genet

Date 2021 May 10

PMID 33968128

Citations 20

Authors

Osman Sharifi

Dag H Yasui

Affiliations

Soon will be listed here.

Abstract

MeCP2 protein, encoded by the gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As 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 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) 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.

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References

McMahon A, Rahman R, Jin H, Shen J, Fieldsend A, Luo W . TRIBE: Hijacking an RNA-Editing Enzyme to Identify Cell-Specific Targets of RNA-Binding Proteins. Cell. 2016; 165(3):742-53. PMC: 5027142. DOI: 10.1016/j.cell.2016.03.007. View

Valinluck V, Liu P, Kang Jr J, Burdzy A, Sowers L . 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). Nucleic Acids Res. 2005; 33(9):3057-64. PMC: 1140371. DOI: 10.1093/nar/gki612. View

Zoghbi H . MeCP2 dysfunction in humans and mice. J Child Neurol. 2005; 20(9):736-40. DOI: 10.1177/08830738050200090701. View

Millar-Buchner P, Philp A, Gutierrez N, Villanueva S, Kerr B, Flores C . Severe changes in colon epithelium in the Mecp2-null mouse model of Rett syndrome. Mol Cell Pediatr. 2016; 3(1):37. PMC: 5116442. DOI: 10.1186/s40348-016-0065-3. View

Yasui D, Gonzales M, Aflatooni J, Crary F, Hu D, Gavino B . Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome. Hum Mol Genet. 2013; 23(9):2447-58. PMC: 3976336. DOI: 10.1093/hmg/ddt640. View

Maunakea A, Chepelev I, Cui K, Zhao K . Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res. 2013; 23(11):1256-69. PMC: 3817542. DOI: 10.1038/cr.2013.110. View

Weitzel J, Buhrmester H, Stratling W . Chicken MAR-binding protein ARBP is homologous to rat methyl-CpG-binding protein MeCP2. Mol Cell Biol. 1997; 17(9):5656-66. PMC: 232414. DOI: 10.1128/MCB.17.9.5656. View

Sekul E, Moak J, Schultz R, Glaze D, Dunn J, Percy A . Electrocardiographic findings in Rett syndrome: an explanation for sudden death?. J Pediatr. 1994; 125(1):80-2. DOI: 10.1016/s0022-3476(94)70128-8. View

Kerr B, Alvarez-Saavedra M, Saez M, Saona A, Young J . Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice. Hum Mol Genet. 2008; 17(12):1707-17. DOI: 10.1093/hmg/ddn061. View

10.

Ghosh R, Nikitina T, Horowitz-Scherer R, Gierasch L, Uversky V, Hite K . Unique physical properties and interactions of the domains of methylated DNA binding protein 2. Biochemistry. 2010; 49(20):4395-410. PMC: 2872689. DOI: 10.1021/bi9019753. View

11.

Mellen M, Ayata P, Dewell S, Kriaucionis S, Heintz N . MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell. 2012; 151(7):1417-30. PMC: 3653293. DOI: 10.1016/j.cell.2012.11.022. View

12.

Ciernia A, Pride M, Durbin-Johnson B, Noronha A, Chang A, Yasui D . Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering. Hum Mol Genet. 2017; 26(10):1839-1854. PMC: 6075042. DOI: 10.1093/hmg/ddx087. View

13.

Buchmuller B, Kosel B, Summerer D . 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. Sci Rep. 2020; 10(1):4053. PMC: 7055227. DOI: 10.1038/s41598-020-61030-1. View

14.

Zhang P, Ludwig A, Hastert F, Rausch C, Lehmkuhl A, Hellmann I . L1 retrotransposition is activated by Ten-eleven-translocation protein 1 and repressed by methyl-CpG binding proteins. Nucleus. 2017; 8(5):548-562. PMC: 5703239. DOI: 10.1080/19491034.2017.1330238. View

15.

Chahrour M, Jung S, Shaw C, Zhou X, Wong S, Qin J . MeCP2, a key contributor to neurological disease, activates and represses transcription. Science. 2008; 320(5880):1224-9. PMC: 2443785. DOI: 10.1126/science.1153252. View

16.

Muotri A, Marchetto M, Coufal N, Oefner R, Yeo G, Nakashima K . L1 retrotransposition in neurons is modulated by MeCP2. Nature. 2010; 468(7322):443-6. PMC: 3059197. DOI: 10.1038/nature09544. View

17.

Johnson B, Zhao Y, Fasolino M, Lamonica J, Kim Y, Georgakilas G . Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome. Nat Med. 2017; 23(10):1203-1214. PMC: 5630512. DOI: 10.1038/nm.4406. View

18.

Sugino K, Hempel C, Okaty B, Arnson H, Kato S, Dani V . Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes. J Neurosci. 2014; 34(38):12877-83. PMC: 4166166. DOI: 10.1523/JNEUROSCI.2674-14.2014. View

19.

Alessio N, Riccitiello F, Squillaro T, Capasso S, Gaudio S, Di Bernardo G . 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. Exp Mol Med. 2018; 50(3):1. PMC: 6118406. DOI: 10.1038/s12276-017-0005-x. View

20.

Kriaucionis S, Heintz N . The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009; 324(5929):929-30. PMC: 3263819. DOI: 10.1126/science.1169786. View