MECP2 genomic structure and function: insights from ENCODE

Singh, Jasmine; Saxena, Alka; Christodoulou, John; Ravine, David

doi:10.1093/nar/gkn591

Cited by 50 publications

(41 citation statements)

References 102 publications

(180 reference statements)

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“…The authors also reported the presence of two negative regulatory elements [(−309 to −370) and (−553 to −681)] and one positive regulatory element (−847 to −1,071) in the promoter region upstream of the MECP2 exon 1 (−1,071 to +9), activity of which are cell-type specific (Liu and Francke 2006). Later on, another study on the encyclopedia of DNA elements (ENCODE) [http://genome.ucsc.edu/] for MECP2/Mecp2 gene showed that the same promoter region and upstream of that region harbors binding sites for transcription factors such as SP1, SP3, TAP1, RNA Pol II, C/EBP, E2F1 and CTCF, binding of which were confirmed by chromatin immunoprecipitation experiments in different cell lines (Singh et al 2008). Adachi et al, in 2005 reported that only a segment of Mecp2 promoter (−677/−56) is essential to drive the Mecp2 expression in neuronal cell lines and cortical neurons (Adachi et al 2005).…”

Section: Promoter Elementsmentioning

confidence: 88%

“…Chromatin immunoprecipitation results shown in ENCODE demonstrate unique distribution of histone PTMs throughout the MECP2/Mecp2 gene. For example, active histone marks H3K4me2 and H3K4me3 are clustered around the transcription start sites of MECP2/Mecp2 [ (Singh et al 2008) and (http://genome.ucsc.edu/)]. Further showing the role of histone acetylation in regulating MECP2 expression in glioma cells, inhibition of HDAC activity by valproic acid induced MECP2 transcript expression in a time-dependent manner (Kim et al 2008).…”

Section: Histone Posttranslational Modificationsmentioning

confidence: 99%

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Rett Syndrome and MeCP2

2014

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Rett syndrome (RTT) is a severe and progressive neurological disorder, which mainly affects young females. Mutations of the methyl-CpG binding protein 2 (MECP2) gene are the most prevalent cause of classical RTT cases. MECP2 mutations or altered expression are also associated with a spectrum of neurodevelopmental disorders such as autism spectrum disorders with recent links to fetal alcohol spectrum disorders. Collectively, MeCP2 relation to these neurodevelopmental disorders highlights the importance of understanding the molecular mechanisms by which MeCP2 impacts brain development, mental conditions, and compromised brain function. Since MECP2 mutations were discovered to be the primary cause of RTT, a significant progress has been made in the MeCP2 research, with respect to the expression, function and regulation of MeCP2 in the brain and its contribution in RTT pathogenesis. To date, there have been intensive efforts in designing effective therapeutic strategies for RTT benefiting from mouse models and cells collected from RTT patients. Despite significant progress in MeCP2 research over the last few decades, there is still a knowledge gap between the in vitro and in vivo research findings and translating these findings into effective therapeutic interventions in human RTT patients. In this review, we will provide a synopsis of Rett syndrome as a severe neurological disorder and will discuss the role of MeCP2 in RTT pathophysiology.

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Section: Promoter Elementsmentioning

confidence: 88%

Section: Histone Posttranslational Modificationsmentioning

confidence: 99%

Rett Syndrome and MeCP2

2014

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“…However, MECP2 has a higher level of complexity than originally believed [29]. MECP2 has been coimmunoprecipitated with the silencing mediator for retinoid and TH receptors [30].…”

Section: Discussionmentioning

confidence: 99%

Thyroid Function in Rett Syndrome

Stagi

Cavalli²,

Congiu³

et al. 2015

Horm Res Paediatr

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Introduction: Thyroid function in Rett syndrome (RTT) has rarely been studied with unanimous results. However, this aspect is of great concern regarding the effect thyroid hormones (TH) have on proper mammalian brain development. Objective: To evaluate the prevalence of abnormalities of thyroid function in a cohort of children with RTT. Patients and Methods: Forty-five consecutive Caucasian girls (mean age: 8.6 ± 5.3 years, range: 2.0-26.1) meeting the clinical criteria for RTT were recruited. In all of the subjects, we evaluated the serum concentrations of free-T₃ (FT₃), free-T₄ (FT₄), thyroid-stimulating hormone (TSH), thyroperoxidase autoantibodies, thyroglobulin autoantibodies (TgA), and TSH receptor (TSHr) autoantibodies. The results were compared with a group of 146 age-matched healthy Caucasian children and adolescent girls (median age: 9.5 years, range: 1.8-14.6) from the same geographical area. Results: Mean FT₃ and TSH levels were not significantly different between the RTT patients and controls. Nevertheless, FT₄ levels were significantly higher in RTT patients than in controls (p < 0.005). In particular, 17.7% showed FT₄ levels higher than the upper reference limit (vs. 0.7% of controls, p < 0.0001), whereas 12 patients (26.7%) showed higher FT₃ levels than the upper reference limit, significantly differing in respect to controls (2.0%, p < 0.0001). Finally, 5 patients (11.1%) showed higher levels of TSH, statistically differing from the control subjects (2.0%, p < 0.0001). However, evaluating the patients on the basis of different RTT genotype subgroups, patients with CDKL5 deletions showed significantly higher FT₄ values than patients with MeCP2 deletions (p < 0.05). On the other hand, patients with other types of MeCP2 mutations also showed FT₄ levels significantly higher than patients with MeCP2 deletions (p < 0.05). In fact, out of 8 patients with FT₄ levels higher than the upper references limit, 3 of them presented with CDKL5 deletions (3 patients, 37.5%), 4 (50%) had MeCP2 mutations, and 1 (12.5%) belonged to the subgroup of MeCP2 deletions. However, when analyzing FT₃ levels of the 12 patients showing higher FT₃ levels than the upper references limit, 6 (50%) belonged to the subgroup with MeCP2 mutations, 4 (33.3%) to the subgroup with MeCP2 deletions, and 2 (16.7%) to the subgroups with CDKL5 deletions. Furthermore, no patient with RTT was positive for antithyroglobulin autoantibodies, antithyroid peroxidase, or anti-TSHr, with no statistical differences in respect to the controls. L-thyroxine treatment was not necessary for any patient. Conclusions: Abnormalities of thyroid function are not rare in RTT. The possible relationship between these disorders and the RTT phenotype should be confirmed and studied. Children with RTT should be screened for potential thyroid dysfunction.

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“…Studies have shown that the MBD tailor a wedge-shaped molecular structure as shown in figure 4.1.It contains a hydrophobic pocket having the side chains Tyr123 and Ile125 present on the beta-sheet face is thesite of contact with the Methyl groups of the cytosine residues (Wakefieldet al, 1999).The N-terminus of the MBD consist of amino acid identical the HMG (high mobility group proteins) that regulate DNA activities such as transcription, translation etc. Recently the interaction between the N-terminal region and theRepressive Chromatin Regulator Heterochromatin protein 1 (HP1) has been shown which is the key factor in formation of transcriptionally inactive heterochromatin (Singh et al, 2008). …”

Section: The Methyl-cpg Binding Domain (Mbd)mentioning

confidence: 99%