Global Transcriptional and Translational Repression in Human-embryonic-stem-cell-derived Rett Syndrome Neurons

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Oct 8

PMID 24094325

Citations 183

Authors

Yun Li

Haoyi Wang

Julien Muffat

Albert W Cheng

David A Orlando

Jakob Loven

Show-Ming Kwok

Danielle A Feldman

Helen S Bateup

Qing Gao

Dirk Hockemeyer

Maisam Mitalipova

Caroline A Lewis

Matthew G Vander Heiden

Mriganka Sur

Richard A Young

Rudolf Jaenisch

Affiliations

Soon will be listed here.

Abstract

Rett syndrome (RTT) is caused by mutations of MECP2, a methyl CpG binding protein thought to act as a global transcriptional repressor. Here we show, using an isogenic human embryonic stem cell model of RTT, that MECP2 mutant neurons display key molecular and cellular features of this disorder. Unbiased global gene expression analyses demonstrate that MECP2 functions as a global activator in neurons but not in neural precursors. Decreased transcription in neurons was coupled with a significant reduction in nascent protein synthesis and lack of MECP2 was manifested as a severe defect in the activity of the AKT/mTOR pathway. Lack of MECP2 also leads to impaired mitochondrial function in mutant neurons. Activation of AKT/mTOR signaling by exogenous growth factors or by depletion of PTEN boosted protein synthesis and ameliorated disease phenotypes in mutant neurons. Our findings indicate a vital function for MECP2 in maintaining active gene transcription in human neuronal cells.

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References

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

Kriaucionis S, Paterson A, Curtis J, Guy J, Macleod N, Bird A . Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol Cell Biol. 2006; 26(13):5033-42. PMC: 1489175. DOI: 10.1128/MCB.01665-05. View

Nan X, Campoy F, Bird A . MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997; 88(4):471-81. DOI: 10.1016/s0092-8674(00)81887-5. View

Tullai J, Schaffer M, Mullenbrock S, Sholder G, Kasif S, Cooper G . Immediate-early and delayed primary response genes are distinct in function and genomic architecture. J Biol Chem. 2007; 282(33):23981-95. PMC: 2039722. DOI: 10.1074/jbc.M702044200. View

Kugler S, Kilic E, Bahr M . Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Ther. 2003; 10(4):337-47. DOI: 10.1038/sj.gt.3301905. View

Yasui D, Peddada S, Bieda M, Vallero R, Hogart A, Nagarajan R . Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc Natl Acad Sci U S A. 2007; 104(49):19416-21. PMC: 2148304. DOI: 10.1073/pnas.0707442104. View

Chen R, Akbarian S, TUDOR M, Jaenisch R . Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet. 2001; 27(3):327-31. DOI: 10.1038/85906. View

Chambers S, Fasano C, Papapetrou E, Tomishima M, Sadelain M, Studer L . Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009; 27(3):275-80. PMC: 2756723. DOI: 10.1038/nbt.1529. View

Ananiev G, Williams E, Li H, Chang Q . Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS One. 2011; 6(9):e25255. PMC: 3180386. DOI: 10.1371/journal.pone.0025255. View

10.

Thoreen C, Chantranupong L, Keys H, Wang T, Gray N, Sabatini D . A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012; 485(7396):109-13. PMC: 3347774. DOI: 10.1038/nature11083. View

11.

Ricciardi S, Boggio E, Grosso S, Lonetti G, Forlani G, Stefanelli G . Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet. 2011; 20(6):1182-96. DOI: 10.1093/hmg/ddq563. View

12.

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

13.

Pagliarini D, Calvo S, Chang B, Sheth S, Vafai S, Ong S . A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008; 134(1):112-23. PMC: 2778844. DOI: 10.1016/j.cell.2008.06.016. View

14.

Sansal I, Sellers W . The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004; 22(14):2954-63. DOI: 10.1200/JCO.2004.02.141. View

15.

Pirooznia M, Wang T, Avramopoulos D, Valle D, Thomas G, Huganir R . SynaptomeDB: an ontology-based knowledgebase for synaptic genes. Bioinformatics. 2012; 28(6):897-9. PMC: 3307115. DOI: 10.1093/bioinformatics/bts040. View

16.

Anguera M, Sadreyev R, Zhang Z, Szanto A, Payer B, Sheridan S . Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell Stem Cell. 2012; 11(1):75-90. PMC: 3587778. DOI: 10.1016/j.stem.2012.03.008. View

17.

Su D, Cha Y, West A . Mutation of MeCP2 alters transcriptional regulation of select immediate-early genes. Epigenetics. 2012; 7(2):146-54. PMC: 3335908. DOI: 10.4161/epi.7.2.18907. View

18.

Cornford M, Philippart M, Jacobs B, SCHEIBEL A, Vinters H . Neuropathology of Rett syndrome: case report with neuronal and mitochondrial abnormalities in the brain. J Child Neurol. 1994; 9(4):424-31. DOI: 10.1177/088307389400900419. View

19.

Luikart B, Schnell E, Washburn E, Bensen A, Tovar K, Westbrook G . Pten knockdown in vivo increases excitatory drive onto dentate granule cells. J Neurosci. 2011; 31(11):4345-54. PMC: 3113533. DOI: 10.1523/JNEUROSCI.0061-11.2011. View

20.

Li Y, Yui D, Luikart B, McKay R, Li Y, Rubenstein J . Conditional ablation of brain-derived neurotrophic factor-TrkB signaling impairs striatal neuron development. Proc Natl Acad Sci U S A. 2012; 109(38):15491-6. PMC: 3458400. DOI: 10.1073/pnas.1212899109. View