Genetic Modifiers of MeCP2 Function in Drosophila

Cukier, Holly N.; Pérez, Alma M.; Collins, Andrew; Zhou, Zhaolan; Zoghbi, Huda Y.; Botas, Juan

doi:10.1371/journal.pgen.1000179

Cited by 69 publications

(83 citation statements)

References 58 publications

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“…In this model, formation of additional veins on the L3, -4 and -5 vasculature were observed (Fig. 1E), and these results were consistent with a previous report (Cukier et al, 2008). In addition, when hMeCP2 was expressed in the whole body under da-Gal4 driver, larval growth was inhibited (data not shown) and the individual died accompanied by melanization in the caudal region at the moment of pupariation (180 h after egg laying) at 25°C (Fig.…”

Section: Binding Of Human Mecp2 To Drosophila Chromatinsupporting

confidence: 92%

“…The chromatin remodeling factors are conserved in Drosophila and mammal (Ho and Crabtree, 2011), although Drosophila has a different methylation site compared to mammals (Marhold et al, 2004), and the ortholog of MeCP2 has not been reported to exist in Drosophila. hMeCP2 protein was reported to genetically interact with several Drosophila chromatin remodeling factors, such as Additional sex combs (Asx), osa, pebble (pbl), and trithorax (trx) (Cukier et al, 2008). Therefore, our data suggest the possibility that hMeCP2 regulates stem cell proliferation via the modulation or/and interaction of chromatin remodeling factors independent with binding to methylated DNA.…”

Section: Discussionmentioning

confidence: 66%

“…Although Drosophila has a different DNA methylation site compared to mammals (Marhold et al, 2004) and the ortholog of MeCP2 has not been reported to exist in Drosophila, the chromatin remodeling factors are conserved in Drosophila and mammal (Ho and Crabtree, 2011). Furthermore, transgenic Drosophila was recently used to identify modifiers involved in the rough eye phenotype induced by overexpression of human MeCP2 (hMeCP2) (Cukier et al, 2008), suggesting that the transgenic Drosophila approach is suitable for investigating the function of hMeCP2 in vivo. Therefore, in this study we investigated the physiological role of epigenetic factor, hMeCP2 in ISC proliferation, using transgenic Drosophila model.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Intestinal Stem Cell Proliferation by Human Methyl-CpG-binding Protein-2 in Drosophila

Lee

Kim

et al. 2011

Cell Struct. Funct.

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ABSTRACT. Recent studies have suggested the involvement of epigenetic factors such as methyl-CpG-binding protein-2 (MeCP2) in tumorigenesis. In addition, cancer may represent a stem cell-based disease, suggesting that understanding of stem cell regulation could provide valuable insights into the mechanisms of tumorigenesis. However, the function of epigenetic factors in stem cell regulation in adult tissues remains poorly understood. In the present study, we investigated the role of human MeCP2 (hMeCP2), a bridge factor linked to DNA modification and histone modification, in stem cell proliferation using adult Drosophila midgut, which appears to be an excellent model system to study stem cell biology. Results show that enterocyte (EC)-specific expression of hMeCP2 in adult midgut using an exogenous GAL4/UAS expression system induced intestinal stem cell (ISC) proliferation marked by staining with anti-phospho-histone H3 antibody and BrdU incorporation assays. In addition, hMeCP2 expression in ECs activated extracellular stress-response kinase signals in ISCs. Furthermore, expression of hMeCP2 modulated the distribution of heterochromatin protein-1 in ECs. Our data suggests the hypothesis that the expression of hMeCP2 in differentiated ECs stimulates ISC proliferation, implying a role of MeCP2 as a stem cell regulator.

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Section: Binding Of Human Mecp2 To Drosophila Chromatinsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of Intestinal Stem Cell Proliferation by Human Methyl-CpG-binding Protein-2 in Drosophila

Lee

Kim

et al. 2011

Cell Struct. Funct.

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“…These experimental results are unanticipated but not unprecedented. MeCP2 has also been distinguished with the expression of gene activity, furthermore raising the intriguing possibility of a multifunctional role for MeCP2 (Cukier et al, 2008). These studies present a complicated and even contradictory set of experimental data on the binding preferences for MeCP2 and its regulatory roles in transcription (Weitzel et The MeCP2 molecule has only a 2-3-fold preference for methylated over unmethylated sequences (Hite et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…The existing literature suggests a multifunctional role for MeCP2 in regulating gene activity. These recent studies have also brought to light additional experimental information and the intriguing possibility that the MeCP2 regulatory complex could be involved in the repression of unmethylated genes (Cukier et al, 2008). In view of these observations, the emerging picture is one of remarkable complexity for MeCP2.…”

Section: Slc6a2 Promoter Is Hypomethylatedmentioning

confidence: 95%

Alleviating Transcriptional Inhibition of the NorepinephrineSlc6a2Transporter Gene in Depolarized Neurons

Kaipananickal¹,

Bayles²,

Ciccotosto³

et al. 2010

J. Neurosci.

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Recent studies have brought to light additional experimental information, namely, that the MeCP2 protein complex is not only capable of associating with members of the ATPase-dependent bromodomain family, but also found on nonmethylated genomic sequences. These unexpected results are indicative of a multifunctional role for MeCP2, more importantly; our view of the molecular mechanisms that regulate gene activity may not be necessarily distinguishable. Depolarized mouse neuronal cortical cells were examined for increased Slc6a2 mRNA synthesis, changes in CpG methylation status using bisulfite sequencing, and binding of MeCP2 and Smarca2 on the Slc6a2 promoter sequence by chromatin immunopurification strategies. Increased Slc6a2 gene expression in response to membrane depolarization was strongly correlated with the dissociation of MeCP2 and Smarca2 complex on the unmethylated gene. We identified that gene expression in neuronal cortical cells involves increased histone hyperacetylation on the Slc6a2 promoter, which is commensurate with the recruitment of SP1 and RNA Polymerase II and is inversely correlated with H3K9 trimethylation. We hypothesize that the MeCP2 corepressor is capable of associating with multiple forms of SWI/SNF to remodel chromatin for important regulatory roles. The results of our experiments indicate that these proteins are asymmetrically bound to chromatin independent of DNA methylation and not inevitably diametrically opposed. These results now begin to offer a new perspective on the mechanism of Slc6a2 gene regulation.

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D rosophila as a Model for Human Diseases

Marcogliese

Wangler

2018

Encyclopedia of Life Sciences

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The fruit fly has long been a powerful organism for high‐throughput in vivo studies in biology and genetics. Studies in Drosophila offer a simple platform, modelling multiple human diseases. With an ever‐expanding genetic toolkit, the fly genome has become increasingly accessible to experimental manipulation. The ectopic expression of human disease genes involved in neurodegenerative and neurodevelopmental disorders have elucidated genetic modifiers that have been revealed to also cause human disease or to be potential drug targets for human neurological disorders. Recently, fly models are being used to study other human pathology such as cancer, infections and cardiovascular disorders. Lastly, ‘humanisation’ strategies to replace endogenous fly genes with their human homologue have begun. This has been particularly beneficial in assessing putative pathogenic variants implicated in rare Mendelian disorders, and thereby aiding diagnosis. In summary, the fly has remained a relevant platform for modelling human disease and elucidating genetic pathways and potential therapeutic targets. Key Concepts There is a vast, ever‐expanding genetic toolkit for manipulation of genes in the fly. Significant advances have been made to further understanding a wide range of human diseases through studies of fly models. Humanisation via use of the T2A‐GAL4 system along with UAS human cDNA transgenics provide a method to test variants implicated in human disease. Flies can be used to study common neurodegenerative diseases as well as rare Mendelian disorders. Functional testing of putative disease causing variants may still be accomplished in flies even when the phenotype may not overlap with human disease presentation.

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Genetic Modifiers of MeCP2 Function in Drosophila

Cited by 69 publications

References 58 publications

Regulation of Intestinal Stem Cell Proliferation by Human Methyl-CpG-binding Protein-2 in Drosophila

Regulation of Intestinal Stem Cell Proliferation by Human Methyl-CpG-binding Protein-2 in Drosophila

Alleviating Transcriptional Inhibition of the NorepinephrineSlc6a2Transporter Gene in Depolarized Neurons

D rosophila as a Model for Human Diseases

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