The methyl-CpG-binding protein MeCP2 and neurological disease

Bird, Adrian

doi:10.1042/bst0360575

Cited by 60 publications

(51 citation statements)

References 92 publications

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“…Nevertheless by focusing on a single gene it is possible to gain insights into the possible mechanisms whereby HMGN1 affects the global phenotype. We focused on MeCP2 as a gene regulated by HMGN1 because it is highly expressed in brain (23) and because it is well documented that misexpression of MeCP2 or mutations in MeCP2 are strongly linked to behavioral abnormalities in human and mice (55)(56)(57)(58). Our findings that HMGN1 is associated with regulatory regions of MeCP2 in both human and mouse brain tissues and that the MeCP2 levels in brain tissues from mice that either overexpress or lack HMGN1 are either reduced or elevated, respectively, suggest that HMGN1 modulates MeCP2 levels in vivo.…”

Section: Hmgn1mentioning

confidence: 99%

The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

Abuhatzira

Shamir

Schones

et al. 2011

Journal of Biological Chemistry

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Background: HMGN1 is a chromatin-binding protein that modulates the cellular transcription profile. Results: Mice that either overexpress or lack HMGN1 have altered behavioral phenotypes. HMGN1 is a negative regulator of MeCP2, a protein involved in neurodevelopmental disorders. Conclusion: Misregulation of HMGN1 protein levels lead to behavioral changes in mice. Significance: HMGN1 is an epigenetic factor that contributes to the development of neurodevelopmental disorders.

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Section: Hmgn1mentioning

confidence: 99%

The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

Abuhatzira

Shamir

Schones

et al. 2011

Journal of Biological Chemistry

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“…The role of this transcription factor is incompletely understood. Until recently, on the basis of animal studies primarily in embryonic or early neonatal brain, Mecp2 was considered a translational repressor (2,3). Recently, however, Skene et al (4) found in neuronal nuclei of mature (6-8 wk) WT littermates of Mecp2 null males that Mecp2 expression is ≈fivefold greater than that at birth.…”

mentioning

confidence: 99%

Correction of respiratory disorders in a mouse model of Rett syndrome

Abdala

Dutschmann

Bissonnette

et al. 2010

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

150

159

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Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome.R ett syndrome (RTT) is an autism spectrum disorder that is caused by mutations in the X-linked gene that encodes methyl-CpG-binding protein 2 (MeCP2) (1). The role of this transcription factor is incompletely understood. Until recently, on the basis of animal studies primarily in embryonic or early neonatal brain, Mecp2 was considered a translational repressor (2, 3). Recently, however, Skene et al. (4) found in neuronal nuclei of mature (6-8 wk) WT littermates of Mecp2 null males that Mecp2 expression is ≈fivefold greater than that at birth. The amount of Mecp2 bound to DNA was proportional to the methylation density of CpG sequences. Importantly, in adult mice, it has been shown that restoring Mecp2 reverses the abnormalities in mobility, gait, hind limb clasping, tremor, breathing, and general condition that they developed during the period that the transcription factor was deficient (5). Thus, Mecp2 deficiency does not cause neuronal degeneration, nor is it necessary for the correct development of neuronal networks. Strategies aimed at pharmacological corrections of symptoms are therefore essential in treating RTT.Respiratory disorders are prominent and one of the most disturbing features of RTT (6, 7). These abnormalities are faithfully mimicked in mouse models of RTT (8). In Mecp2 null male animals studied in situ phrenic (PN) apneas were characterized by prolonged postinspiratory (post-I) activity in the central vagus nerve (9). Post-I activity is linked to the control of laryngeal adductors that control expiratory airflow and protect the lower airways from aspiration during swallowing. Active breath-hold with laryngeal closure is a common feature of RTT (6,7,10).This raises the possibility that the apneas are due to overactive brainstem expiratory neurons in Mecp2 heterozygote mice, perhaps consequent to a lack of synaptic inhibitory control. In this regard, examination of GABA synaptic inhibition in the ventrolateral medulla of Mec...

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“…It also involves chromatin components and chromatin-binding/-modifying proteins, which are implicated in the establishment and maintenance of a condensed chromatin state, also referred to as facultative heterochromatin (1). Deregulation of these chromatin regulatory factors and aberrant chromatin modifications play important roles in various human diseases, including cancers, developmental abnormalities, and neurologic disorders (2)(3)(4)(5)(6). Moreover, several recent reports have linked histone modifications and infectious diseases (7).…”

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confidence: 99%

Human BAHD1 promotes heterochromatic gene silencing

Bierne

Tham

Batsché

et al. 2009

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

125

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Gene silencing via heterochromatin formation plays a major role in cell differentiation and maintenance of homeostasis. Here we report the identification and characterization of a novel heterochromatinization factor in vertebrates, bromo adjacent homology domaincontaining protein 1 (BAHD1). This nuclear protein interacts with HP1, MBD1, HDAC5, and several transcription factors. Through electron and immunofluorescence microscopy studies, we show that BAHD1 overexpression directs HP1 to specific nuclear sites and promotes the formation of large heterochromatic domains, which lack acetyl histone H4 and are enriched in H3 trimethylated at lysine 27 (H3K27me3). Furthermore, ectopically expressed BAHD1 colocalizes with the heterochromatic inactive X chromosome (Xi). The BAH domain is required for BAHD1 colocalization with H3K27me3, but not with the Xi chromosome. As highlighted by whole genome microarray analysis of BAHD1 knockdown cells, BAHD1 represses several proliferation and survival genes, in particular the insulin-like growth factor II gene (IGF2). When overexpressed, BAHD1 specifically binds the CpG-rich P3 promoter of IGF2, which increases MBD1 and HDAC5 targeting at this locus. This region contains DNA-binding sequences for the transcription factor SP1, with which BAHD1 coimmunoprecipitates. Collectively, these findings provide evidence that BAHD1 acts as a silencer by recruiting at specific promoters a set of proteins that coordinate heterochromatin assembly.BAH domain ͉ epigenetics ͉ heterochromatin ͉ HP1 ͉ polycomb G ene repression in eukaryotes in response to developmental or environmental signals is a complex multistep process requiring the concerted action of many cellular factors, including DNA-binding transcription factors and cofactors. It also involves chromatin components and chromatin-binding/-modifying proteins, which are implicated in the establishment and maintenance of a condensed chromatin state, also referred to as facultative heterochromatin (1). Deregulation of these chromatin regulatory factors and aberrant chromatin modifications play important roles in various human diseases, including cancers, developmental abnormalities, and neurologic disorders (2-6). Moreover, several recent reports have linked histone modifications and infectious diseases (7). During a screen for human proteins that interact with microbial factors and that might play a role in bacterial pathogenicity, we identified a putative chromatin-associated protein, bromo adjacent homology domaincontaining protein 1 (BAHD1), which remains uncharacterized. One study correlated repression of the BAHD1 gene to poor prognosis in lung cancer (8), raising the possibility that BAHD1 might act as a tumor suppressor. This connection between BAHD1 and pathological processes prompted us to characterize the function of this protein.BAHD1 is so named because it contains a C-terminal BAH domain, which is found in several chromatin-binding proteins involved in transcriptional repression (9), including the yeast Sir3 protein (10). We invest...

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The methyl-CpG-binding protein MeCP2 and neurological disease

Cited by 60 publications

References 92 publications

The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

The Chromatin-binding Protein HMGN1 Regulates the Expression of Methyl CpG-binding Protein 2 (MECP2) and Affects the Behavior of Mice

Correction of respiratory disorders in a mouse model of Rett syndrome

Human BAHD1 promotes heterochromatic gene silencing

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