Neuronal MeCP2 Is Expressed at Near Histone-Octamer Levels and Globally Alters the Chromatin State

Skene, Peter J.; Illingworth, Robert S.; Webb, Shaun; Kerr, Alastair; James, Keith; Turner, Daniel J.; Andrews, Robert J.; Bird, Adrian

doi:10.1016/j.molcel.2010.01.030

Cited by 609 publications

(808 citation statements)

References 45 publications

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“…Notons que le petit nombre de gènes cibles directs découverts à ce jour met à mal l'hypothèse d'un rôle de répresseur global du génome pour MeCP2, qui servirait à réduire le bruit de fond transcriptionnel général [30]. Si, au contraire, le rôle de MeCP2 était de répri-mer quelques gènes parfaitement ciblés, ce phénomène reviendrait à réinterpréter la méthylation de l'ADN.…”

Section: Les Gènes Cibles De Mecp2unclassified

Addiction et régulations épigénétiques

Zwiller

2015

Med Sci (Paris)

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> L'administration répétée de drogues entraîne, dans certaines structures cérébrales, une importante plasticité synaptique dont la mise en place et le maintien nécessitent l'expression de nombreux gènes. L'hypothèse proposée ici est que des régulations épigénétiques participent à l'installation de ces adaptations persistantes. Le point est fait sur la question de la méthylation de l'ADN en réponse aux drogues, et l'accent sera mis sur la protéine MeCP2 (methyl-CpGbinding protein 2), qui se lie à l'ADN méthylé. L'implication de l'acétylation des histones dans le mode d'action des drogues est discutée. Ces régulations représentent potentiellement de nouvelles cibles thérapeutiques pour le traitement de la dépendance aux drogues. < Bien qu'un grand nombre d'individus consomment régulièrement des drogues, seule une minorité de consommateurs réguliers passent dans une phase de consommation compulsive. Le passage dans cette phase est largement influencé par des facteurs de susceptibilité génétique, et par le contexte social et psychologique de l'individu. Alors que le risque d'ordre génétique de développement d'une addiction est estimé à environ 50 %, les gènes responsables ne sont pas bien connus [5,53] ( §). Une part importante de la recherche se concentre donc sur la composante environnementale. L'hypothèse privilégiée dans ce domaine veut que la transition vers un état de dépendance résulte de processus adaptatifs qui se mettent en place dans certaines structures cérébrales en réponse à des prises répétées de la substance [6]. Les mécanismes d'adaptation ont souvent été décrits comme des réponses compensatrices servant à faire revenir le système à son état basal. Ce mécanisme, défini comme une rétroac-tion négative, peut expliquer l'apparition du phénomène de tolérance (correspondant au fait que des doses croissantes sont nécessaires pour maintenir des effets comparables), voire de certains symptômes apparaissant lors du sevrage. D'autres mécanismes d'adaptation semblent produire une rétroaction positive, qui pourrait rendre compte du phéno-mène de sensibilisation comportementale (voir Encadré page suivante). On peut aussi envisager des changements qualitatifs, qui altéreraient la réponse à des stimulus autres que le seul stimulus initiateur. Parmi les bouleversements se produisant dans le cerveau lors de prises répétées La dépendance aux droguesLa dépendance aux drogues désigne un état psychologique et/ou physique qui se manifeste par un besoin irrépressible et répété, jamais réellement assouvi, de consommation d'une drogue. Elle est caractérisée par un comportement compulsif de prise de la substance, malgré les lourdes conséquences que ce comportement entraîne sur un plan familial, social, professionnel, ce dont le sujet est conscient [1,2]. Dans une perspective aussi bien psychologique que neurologique, la dépendance peut être considérée comme un trouble de la cognition [3]. En effet, les régions du cerveau et les processus sous-jacents à la dépendance sont aussi ceux qui sont impliqués dans les fonctions cogn...

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Section: Les Gènes Cibles De Mecp2unclassified

Addiction et régulations épigénétiques

Zwiller

2015

Med Sci (Paris)

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“…For example, several studies explored chromatin structures and synaptic signaling in neuronal cultures of Rett syndrome patients with MECP2 mutations and controls (Farra et al, 2012;Muotri et al, 2010). The MECP2 gene product, methyl-CpG-binding protein 2, is highly expressed in the nervous system and occupies widespread territories of neuronal chromatin, dependent on the local density of methyl-CpG-dinucleotides (Skene et al, 2010). Loss-of-function mutations and other MECP2 structural variants have been linked to Rett syndrome, a disorder of early childhood associated with developmental ............................................................................................................................................................ and cognitive regression and a broad range of neurological symptoms (Amir et al, 1999;Chouery et al, 2011).…”

Section: Psychiatric Epigenetics In the Culture Dish?mentioning

confidence: 99%

“…The molecular and cellular mechanisms linking MECP2 mutations to neuronal dysfunction and brain disease remain incompletely understood. Importantly, work on reprogrammed skin cells of Rett patients and Mecp2 mutant mouse brain associates loss of MeCP2 function with disinhibition and increased genomic mobility of retrotransposon and other parasitic DNA element activities because of altered DNA and histone methylation, in conjunction with changes in the global chromatin state (Muotri et al, 2010;Skene et al, 2010). This work illustrates the promising potential of neural cultures, derived from skin fibroblasts, to study epigenetic (dys) regulation in specific disease cases and to gain knowledge about the molecular underpinnings of neurological disorders.…”

Section: Psychiatric Epigenetics In the Culture Dish?mentioning

confidence: 99%

Epigenetics in the Human Brain

Houston

Peter

Mitchell

et al. 2012

Neuropsychopharmacol

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Many cellular constituents in the human brain permanently exit from the cell cycle during pre-or early postnatal development, but little is known about epigenetic regulation of neuronal and glial epigenomes during maturation and aging, including changes in mood and psychosis spectrum disorders and other cognitive or emotional disease. Here, we summarize the current knowledge base as it pertains to genome organization in the human brain, including the regulation of DNA cytosine methylation and hydroxymethylation, and a subset of (altogether 4100) residue-specific histone modifications associated with gene expression, and silencing and various other functional chromatin states. We propose that high-resolution mapping of epigenetic markings in postmortem brain tissue or neural cultures derived from induced pluripotent cells (iPS), in conjunction with transcriptome profiling and whole-genome sequencing, will increasingly be used to define the molecular pathology of specific cases diagnosed with depression, schizophrenia, autism, or other major psychiatric disease. We predict that these highly integrative explorations of genome organization and function will provide an important alternative to conventional approaches in human brain studies, which mainly are aimed at uncovering group effects by diagnosis but generally face limitations because of cohort size.

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“…MeCP2 | NCoR/SMRT | Rett syndrome | TBL proteins | intellectual disability T he methyl-CpG-binding protein 2 (MeCP2) is a chromatinassociated factor that is highly expressed in the brain (1,2). Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls.…”

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confidence: 99%

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Kruusvee

Lyst

Taylor

et al. 2017

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

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Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.T he methyl-CpG-binding protein 2 (MeCP2) is a chromatinassociated factor that is highly expressed in the brain (1, 2). Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls. In addition, extra copies of the gene cause MeCP2 duplication syndrome (4, 5), a distinct intellectual disability disorder that predominantly affects males (6). The importance of MeCP2 for brain function has prompted investigation of its molecular function. The protein was identified because of its ability to bind DNA via its methyl-CpG-binding domain (MBD) (1, 7) and many residues mutated in RTT disrupt this interaction (8-11). In addition to DNA, numerous protein partners of MeCP2 have been reported (11). Of these protein partners, only the interactions with the nuclear receptor corepressor (NCoR) and its close relative silencing mediator of retinoic acid and thyroid receptors (SMRT) (12-14) are known to be disrupted by RTT missense mutations (13). Accordingly, Rett missense mutations outside the MBD are found clustered within the so-called "NCoR/SMRT interaction domain" (NID) (13) (Fig. 1A and Fig. S1A). One NID mutation, R306C, causes a severe RTT-like phenotype in mice (13,15,16). Moreover, mouse models of MeCP2 duplication syndrome suggest that both the MBD and the NID must be intact for this adverse molecular pathology to develop (16,17).These findings indicate that the NID mediates an essential function of MeCP2. This function may be recruitment of the NCoR/ SMRT corepressor complexes to chromatin. Alternatively, the NID may perform other essential roles, such as DNA binding, whose loss leads to RTT (16). In an attempt to distinguish among these possibilities, we investigated the molecular basis of the interaction between MeCP2 and NCoR/SMRT. The latter are ∼1.2-MDa multisubunit complexes that include NCoR1 (and/or SMRT), HDAC3, GPS2, and...

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Neuronal MeCP2 Is Expressed at Near Histone-Octamer Levels and Globally Alters the Chromatin State

Cited by 609 publications

References 45 publications

Addiction et régulations épigénétiques

Addiction et régulations épigénétiques

Epigenetics in the Human Brain

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

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