Disease Modeling Using Embryonic Stem Cells: MeCP2 Regulates Nuclear Size and RNA Synthesis in Neurons

Yazdani, Morteza; Deogracias, Rubén; Guy, Jacky; Poot, Raymond A.; Bird, Adrian; Barde, Yves‐Alain

doi:10.1002/stem.1180

Cited by 77 publications

(70 citation statements)

References 38 publications

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“…These results are well aligned with our findings in mecp2 morphants in zebrafish. In addition, recent reports have shown that the soma size is reduced and that there are smaller nuclei in neurons derived from MeCP2-null embryonic stem cells, with active transcription and protein synthesis are reduced (Li et al, 2013;Yazdani et al, 2012). This is consistent with our result that the soma size of motor neurons was reduced in Tg(islet1:GFP) transgenic embryos injected with mecp2-MO (data not shown).…”

Section: Discussionsupporting

confidence: 93%

Mecp2 regulates neural cell differentiation by suppressing the Id1 to Her2 axis in zebrafish

Gao

et al. 2015

Journal of Cell Science

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Rett syndrome (RTT) is a progressive neurological disorder caused by mutations in the X-linked protein methyl-CpG-binding protein 2 (MeCP2). The endogenous function of MeCP2 during neural differentiation is still unclear. Here, we report that mecp2 is required for brain development in zebrafish. Mecp2 was broadly expressed initially in embryos and enriched later in the brain. Either morpholino knockdown or genetic depletion of mecp2 inhibited neuronal differentiation, whereas its overexpression promoted neuronal differentiation, suggesting an essential role of mecp2 in directing neural precursors into differentiated neurons. Mechanistically, her2 (the zebrafish ortholog of mammalian Hes5) was upregulated in mecp2 morphants in an Id1-dependent manner. Moreover, knockdown of either her2 or id1 fully rescued neuronal differentiation in mecp2 morphants. These results suggest that Mecp2 plays an important role in neural cell development by suppressing the Id1-Her2 axis, and provide new evidence that embryonic neural defects contribute to the later motor and cognitive dysfunctions in RTT.

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Section: Discussionsupporting

confidence: 93%

Mecp2 regulates neural cell differentiation by suppressing the Id1 to Her2 axis in zebrafish

Gao

et al. 2015

Journal of Cell Science

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“…This raises the possibility that MeCP2 may not activate genes by a direct mode of action that requires mCA. One of the hallmark features of MeCP2-deficent mouse and human neurons is decreased dendritic branching, soma, and nuclear size (25,26). It has recently been demonstrated that mammalian cells globally scale transcription in a cell-volume-dependent manner to preserve transcript concentration (27).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation in the gene body influences MeCP2-mediated gene repression

Kinde

Greenberg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

112

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Rett syndrome is a severe neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein gene (MECP2). MeCP2 is a methyl-cytosine binding protein that is proposed to function as a transcriptional repressor. However, multiple gene expression studies comparing wild-type and MeCP2-deficient neurons have failed to identify gene expression changes consistent with loss of a classical transcriptional repressor. Recent work suggests that one function of MeCP2 in neurons is to temper the expression of the longest genes in the genome by binding to methylated CA dinucleotides (mCA) within transcribed regions of these genes. Here we explore the mechanism of mCA and MeCP2 in fine tuning the expression of long genes. We find that mCA is not only highly enriched within the body of genes normally repressed by MeCP2, but also enriched within extended megabase-scale regions surrounding MeCP2-repressed genes. Whereas enrichment of mCA exists in a broad region around these genes, mCA together with mCG within gene bodies appears to be the primary driver of gene repression by MeCP2. Disruption of methylation at CA sites within the brain results in depletion of MeCP2 across genes that normally contain a high density of gene-body mCA. We further find that the degree of gene repression by MeCP2 is proportional to the total number of methylated cytosine MeCP2 binding sites across the body of a gene. These findings suggest a model in which MeCP2 tunes gene expression in neurons by binding within the transcribed regions of genes to impede the elongation of RNA polymerase.

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“…Recent work investigating the common R306C mutation (found in ~5% of Rett syndrome patients), which falls at the edge of ies have not been performed to distinguish primary and secondary transcriptional effects, the fact that the majority of transcriptional changes are reciprocal between the KO and the MECP2-overexpressing mice suggests a nonrandom sensitivity of genes to MeCP2 function. Further, in contrast to derepression, a global decrease in transcription is observed in neurons derived from mouse and human embryonic stem cells lacking MeCP2 (46,91).…”

Section: From Patient To Protein: the Molecular Function Of Mecp2mentioning

confidence: 96%

MECP2 disorders: from the clinic to mice and back

Lombardi¹,

Baker²,

Zoghbi³

2015

J. Clin. Invest.

193

166

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Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG-binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies.

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Disease Modeling Using Embryonic Stem Cells: MeCP2 Regulates Nuclear Size and RNA Synthesis in Neurons

Cited by 77 publications

References 38 publications

Mecp2 regulates neural cell differentiation by suppressing the Id1 to Her2 axis in zebrafish

Mecp2 regulates neural cell differentiation by suppressing the Id1 to Her2 axis in zebrafish

DNA methylation in the gene body influences MeCP2-mediated gene repression

MECP2 disorders: from the clinic to mice and back

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