Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function

Tao, Jifang; Hu, Keping; Chang, Qiang; Wu, Hao; Sherman, Nicholas E.; Martinowich, Keri; Klose, Robert J.; Schanen, Carolyn; Jaenisch, Rudolf; Wang, Weidong; Sun, Yi

doi:10.1073/pnas.0811648106

Cited by 195 publications

(270 citation statements)

References 37 publications

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“…Interestingly, in MeCP2 mutant mice, a reduction, rather than an increase, of BDNF protein levels was observed (56), suggesting that MeCP2 can also act as a transcription activator. MeCP2 can be modified by phosphorylation, and this modification is considered to direct the function of this DNA-binding protein as a transcriptional repressor or activator (57). RACK1 association with various kinases and phosphatases has been well established (16,58).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Neasta

Ron

2010

Journal of Biological Chemistry

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Scaffolding proteins are major contributors to the spatial and temporal orchestration of signaling cascades and hence cellular functions. RACK1 is a scaffolding protein that plays an important role in the regulation of, and cross-talk between, various signaling pathways. Here we report that RACK1 is a mediator of chromatin remodeling, resulting in an exon-specific expression of the brain-derived neurotrophic factor (BDNF) gene. Specifically, we found that following the activation of the cAMP pathway, nuclear RACK1 localizes at the promoter IV region of the BDNF gene by its association with histones H3 and H4, leading to the dissociation of the transcription repressor methyl-CpGbinding protein 2 (MeCP2) from the promoter, resulting in the acetylation of histone H4. These chromatin modifications lead to the activation of the promoter and to the subsequent promoter-controlled transcription of BDNF exon IV. Our findings expand our knowledge regarding the function of scaffolding proteins such as RACK1. Furthermore, this novel mechanism for the regulation of exon-specific expression of the BDNF gene by RACK1 could have implications on the neuronal functions of the growth factor including synaptic plasticity, learning, and memory.Signal transduction cascades are tightly regulated events. Scaffolding proteins play an essential role in the spatial and temporal regulation of individual enzymes and provide the link between extracellular events and intracellular compartments including the nucleus (1). Scaffolding proteins, by means of protein-protein interactions, provide platforms for protein assembly. The scaffolding protein RACK1, which was originally identified as an anchoring protein of protein kinase C ␤II (2), belongs to the WD40 family of proteins characterized by seven WD40 repeats forming a seven-blade ␤-propeller structure (3, 4). This particular structure allows RACK1 to interact with various enzymes including Fyn kinase (5), focal adhesion kinase (6), receptor protein tyrosine phosphatase (7), the cyclic AMP-specific phosphodiesterase (PDE4) isoform PDE4D5 (8), as well as the intracellular tails of receptors such as the insulin-like growth factor 1 receptor (IGF-1R) (9, 10), the inositol 1,4,5-triphosphate receptor (11), and ion channels such as the NR2B subunit of the N-methyl D-aspartate receptors (5). These interactions, and others, put RACK1 at a focal point for spatial and temporal regulation of various signaling cascades. For example, in transformed cultured cancer cells, RACK1 was shown to form a scaffolding complex that includes the IGF-1R, ␤1 integrin, and focal adhesion kinase (6,9,10,12). In addition, RACK1 is also found at the 40 S ribosomal subunit (3,13,14) and was shown to bridge protein kinase C-mediated signaling to the ribosomal translation machinery (15). RACK1 plays an important role in the central nervous system (16). For example, RACK1 links Fyn kinase to its substrate, the NR2B subunit of the N-methyl D-aspartate receptor (5, 17), and contributes to the regulation of channel activity (18)...

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Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Neasta

Ron

2010

Journal of Biological Chemistry

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“…This activity-dependent phosphorylation of MeCP2 appears to have widespread effects on synaptic plasticity (Li et al, 2011) as mice in which phosphorylation at S421 are lacking display enhancements in LTP, increased excitatory synaptogenesis, as well as improvements in hippocampal-related learning and memory tests (Li et al, 2011). Neuronal activity also triggers dephosphorylation of MeCP2 at serine amino-acid 80 (S80), which alters transcription of various genes (Tao et al, 2009). Although phosphorylation of MeCP2 is implicated as a key regulator of activity-dependent gene expression, there is still much work to do to identify the target genes involved in these critical processes.…”

Section: Regulation Of Neurotransmissionmentioning

confidence: 99%

The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity

Nelson

Kavalali³

et al. 2012

Neuropsychopharmacol

151

116

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Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator of gene expression that is an important epigenetic factor in the maintenance and development of the central nervous system. The neurodevelopmental disorders Rett syndrome and MECP2 duplication syndrome arise from loss-of-function and gain-of-function alterations in MeCP2 expression, respectively. Several animal models have been developed to recapitulate the symptoms of Rett syndrome and MECP2 duplication syndrome. Cell morphology, neurotransmission, and cellular processes that support learning and memory are compromised as a result of MeCP2 loss-or gain-of-function. Interestingly, loss-of-MeCP2 function and MeCP2 overexpression trigger diametrically opposite changes in synaptic transmission. These findings indicate that the precise regulation of MeCP2 expression is a key requirement for the maintenance of synaptic and neuronal homeostasis and underscore its importance in central nervous system function. This review highlights the functional role of MeCP2 in the brain as a regulator of synaptic and neuronal plasticity as well as its etiological role in the development of Rett syndrome and MECP2 duplication syndrome.

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“…MECP2 serves as a balancer in gene regulation: it binds to methylated CpG dinucleotides and recruits histone deacetylase 1 to inactive gene expression [143,144]; while loss of MECP2 in vivo represses the expression of thousands of genes, suggesting that it is a gene activator [145]. The exact mechanism of MECP2 as a gene activator is not yet clear, but there is evidence to show that activity-dependent phosphorylation at S80A and S421A/S424A might account for the fine-tuning of MECP2 functions [146,147].…”

Section: Methyl-cpg-binding Protein 2 Genementioning

confidence: 99%

The complex genetics in autism spectrum disorders

Hua

Wei

Zhang

2015

Sci. China Life Sci.

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Autism spectrum disorders (ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Genetic changes/heritability is one of the major contributing factors, and hundreds to thousands of causative and susceptible genes, copy number variants (CNVs), linkage regions, and microRNAs have been associated with ASD which clearly indicates that ASD is a complex genetic disorder. Here, we will briefly summarize some of the high-confidence genetic changes in ASD and their possible roles in their pathogenesis.autism spectrum disorders, genetics, causative genes, copy number variants Citation:Hua R, Wei MP, Zhang C. The complex genetics in autism spectrum disorders. Sci China Life Sci, 2015, 58: 933 -945,

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Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function

Cited by 195 publications

References 37 publications

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

Epigenetic Regulation of BDNF Expression via the Scaffolding Protein RACK1

The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity

The complex genetics in autism spectrum disorders

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