Regulation and function of stimulus-induced phosphorylation of MeCP2

Li, Hongda; Chang, Qiang

doi:10.1007/s11515-014-1330-2

Cited by 11 publications

(9 citation statements)

References 46 publications

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“…The intrinsically disordered structure of MeCP2 and its several PTMs have been suggested to generate and regulate this functional versatility3137. Several reports have proposed that differential phosphorylation of MeCP2 is a key mechanism by which the protein modulates its affinity for partners and/or DNA1112. However, most of the MeCP2 PTMs studied so far involve almost exclusively the MBD/TRD regions of the protein and phosphorylation sites within the ID have never been characterized.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, mass spectrometry analyses have identified several phosphorylation sites. In neurons, phosphorylation events occur under basal conditions and/or in response to neuronal activity1112. The addition of a negatively charged phosphate group can dramatically impact protein functions.…”

mentioning

confidence: 99%

“…Importantly, a phospho-defective Mecp2 T308A/y knock in mouse line exhibits a large spectrum of neurological symptoms highly phenocopying several mouse models of Mecp2 disorders16. Additionally, it has been proved that MeCP2 phosphorylation impacts dendritic arborization, spine maturation and generally the development and function of the nervous system1112. All these observations highlight the relevance of studying the function and regulation of MeCP2 phosphorylation for advancing our comprehension of RTT and MECP2 related disorders; in particular, we have proposed to start focusing on sites that are evolutionally conserved and/or have been found mutated in patients12.…”

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confidence: 99%

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Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Stefanelli

Gandaglia

Costa

et al. 2016

Sci Rep

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MeCP2 is a transcriptional regulator whose functional alterations are responsible for several autism spectrum and mental disorders. Post-translational modifications (PTMs), and particularly differential phosphorylation, modulate MeCP2 function in response to diverse stimuli. Understanding the detailed role of MeCP2 phosphorylation is thus instrumental to ascertain how MeCP2 integrates the environmental signals and directs its adaptive transcriptional responses. The evolutionarily conserved serine 164 (S164) was found phosphorylated in rodent brain but its functional role has remained uncharacterized. We show here that phosphorylation of S164 in brain is dynamically regulated during neuronal maturation. S164 phosphorylation highly impairs MeCP2 binding to DNA in vitro and largely affects its nucleosome binding and chromatin affinity in vivo. Strikingly, the chromatin-binding properties of the global MeCP2 appear also extensively altered during the course of brain maturation. Functional assays reveal that proper temporal regulation of S164 phosphorylation controls the ability of MeCP2 to regulate neuronal morphology. Altogether, our results support the hypothesis of a complex PTM-mediated functional regulation of MeCP2 potentially involving a still poorly characterized epigenetic code. Furthermore, they demonstrate the relevance of the Intervening Domain of MeCP2 for binding to DNA.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Stefanelli

Gandaglia

Costa

et al. 2016

Sci Rep

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“…Until now, Mecp2’s transcriptional role in cellular and molecular plasticity remains poorly defined, although, an increasing number of posttranslational modifications have been identified (as reviewed elsewhere [ 4 , 83 , 84 ]). Among these, protein (de-) phosphorylation has been most thoroughly studied and is of particular interest to Mecp2’s role in epigenetic programming (see below).…”

Section: Neuronal Activity Controls Mecp2 Via Posttranslational Momentioning

confidence: 99%

Role of Mecp2 in Experience-Dependent Epigenetic Programming

Zimmermann

Hoffmann

Raabe

et al. 2015

Genes

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Mutations in the X-linked gene MECP2, the founding member of a family of proteins recognizing and binding to methylated DNA, are the genetic cause of a devastating neurodevelopmental disorder in humans, called Rett syndrome. Available evidence suggests that MECP2 protein has a critical role in activity-dependent neuronal plasticity and transcription during brain development. Moreover, recent studies in mice show that various posttranslational modifications, notably phosphorylation, regulate Mecp2’s functions in learning and memory, drug addiction, depression-like behavior, and the response to antidepressant treatment. The hypothalamic-pituitary-adrenal (HPA) axis drives the stress response and its deregulation increases the risk for a variety of mental disorders. Early-life stress (ELS) typically results in sustained HPA-axis deregulation and is a major risk factor for stress related diseases, in particular major depression. Interestingly, Mecp2 protein has been shown to contribute to ELS-dependent epigenetic programming of Crh, Avp, and Pomc, all of these genes enhance HPA-axis activity. Hereby ELS regulates Mecp2 phosphorylation, DNA binding, and transcriptional activities in a tissue-specific and temporospatial manner. Overall, these findings suggest MECP2 proteins are so far underestimated and have a more dynamic role in the mediation of the gene-environment dialog and epigenetic programming of the neuroendocrine stress system in health and disease.

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“…The latter modification could couple as well to environmental exposures and life experiences that act as risk factors in AD. For example, the neuronal activity-dependent transcriptional regulator methyl-CpG-binding protein (MeCP2) [88,89] has been recently shown to recognize mCH and to confer transcriptional repression [90]. Intriguingly, MeCP2's role may extend well beyond early development [91] and mediate between different environmental exposures and the epigenome [92].…”

Section: Discussionmentioning

confidence: 99%

Driver or Passenger: Epigenomes in Alzheimer’s Disease

Hoffmann¹,

Sportelli²,

Ziller³

et al. 2017

Epigenomes

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Alzheimer's disease (AD) is a fatal neurodegenerative disease which is on the rise worldwide. Despite a wealth of information, genetic factors contributing to the emergence of AD still remain incompletely understood. Sporadic AD is polygenetic in nature and is associated with various environmental risks. Epigenetic mechanisms are well-recognized in the mediation of gene environment interactions, and analysis of epigenetic changes at the genome scale can offer new insights into the relationship between brain epigenomes and AD. In fact, recent epigenome-wide association studies (EWAS) indicate that changes in DNA methylation are an early event preceding clinical manifestation and are tightly associated with AD neuropathology. Further, candidate genes from EWAS interact with those from genome-wide association studies (GWAS) that can undergo epigenetic changes in their upstream gene regulatory elements. Functionally, AD-associated DNA methylation changes partially influence transcription of candidate genes involved in pathways relevant to AD. The timing of epigenomic changes in AD together with the genes affected indicate a critical role, however, further mechanistic insight is required to corroborate this hypothesis. In this respect, recent advances in neuronal reprogramming of patient-derived cells combined with new genome-editing techniques offer unprecedented opportunities to dissect the functional and mechanistic role of epigenomic changes in AD.

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Regulation and function of stimulus-induced phosphorylation of MeCP2

Cited by 11 publications

References 46 publications

Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association

Role of Mecp2 in Experience-Dependent Epigenetic Programming

Driver or Passenger: Epigenomes in Alzheimer’s Disease

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