Transcriptional regulation by MECP2 (Homo sapiens)
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Methyl-CpG-binding protein 2 encoded by the MECP2 gene binds to methylated CpG sequences in the DNA. The binding is not generic, however, but is affected by the underlying DNA sequence (Yoon et al. 2003). MECP2 binds to DNA containing 5 methylcytosine (5mC DNA), a DNA modification associated with transcriptional repression (Mellen et al. 2012), both in the context of CpG islands and outside of CpG islands (Chen et al. 2015). In addition, MECP2 binds to DNA containing 5 hydroxymethylcytosine (5hmC DNA), a DNA modification associated with transcriptional activation (Mellen et al. 2012). MECP2 binds to DNA as a monomer, occupying about 11 bp of the DNA. Binding of one MECP2 molecule facilitates binding of the second MECP2 molecule, and therefore clustering can occur at target sites. MECP2 binding to chromatin may be facilitated by nucleosome methylation (Ghosh et al. 2010).<p>MECP2 was initially proposed to act as a generic repressor of gene transcription. However, high throughput studies of MECP2-induced changes in gene expression in mouse hippocampus (Chahrour et al. 2008), and mouse and human cell lines (Orlic-Milacic et al. 2014) indicate that more genes are up-regulated than down-regulated when MECP2 is overexpressed. At least for some genes directly upregulated by MECP2, it was shown that a complex of MECP2 and CREB1 was involved in transcriptional stimulation (Chahrour et al. 2008, Chen et al. 2013).<p>MECP2 expression is the highest in postmitotic neurons compared to other cell types, with MECP2 being almost as abundant as core histones. Phosphorylation of MECP2 in response to neuronal activity regulates binding of MECP2 to DNA, suggesting that MECP2 may remodel chromatin in a neuronal activity-dependent manner. The resulting changes in gene expression would then modulate synaptic plasticity and behavior (reviewed by Ebert and Greenberg 2013). In human embryonic stem cell derived Rett syndrome neurons, loss of MECP2 is associated with a significant reduction in transcription of neuronally active genes, as well as the reduction in nascent protein synthesis. The reduction in nascent protein synthesis can at least in part be attributed to the decreased activity of the PI3K/AKT/mTOR signaling pathway. Neuronal morphology (reduced soma size) and the level of protein synthesis in Rett neurons can be ameliorated by treating the cells with growth factors which activate the PI3K/AKT/mTOR cascade or by inhibition of PTEN, the negative regulator of AKT activation. Mitochondrial gene expression is also downregulated in Rett neurons, which is associated with a reduced capacity of the mitochondrial electron transport chain (Ricciardi et al. 2011, Li et al. 2013). Treatment of Mecp2 null mice with IGF1 (insulin-like growth factor 1) reverses or ameliorates some Rett-like features such as locomotion, respiratory difficulties and irregular heart rate (Tropea et al. 2009).<p>MECP2 regulates expression of a number of ligands and receptors involved in neuronal development and function. Ligands regulated by MECP2 include BDNF (reviewed by Li and Pozzo-Miller 2014, and KhorshidAhmad et al. 2016), CRH (McGill et al. 2006, Samaco et al. 2012), SST (Somatostatin) (Chahrour et al. 2008), and DLL1 (Li et al. 2014). MECP2 also regulates transcription of genes involved in the synthesis of the neurotransmitter GABA – GAD1 (Chao et al. 2010) and GAD2 (Chao et al. 2010, He et al. 2014). MECP2 may be involved in direct stimulation of transcription from the GLUD1 gene promoter, encoding mitochondrial glutamate dehydrogenase 1, which may be involved in the turnover of the neurotransmitter glutamate (Livide et al. 2015). Receptors regulated by MECP2 include glutamate receptor GRIA2 (Qiu et al. 2012), NMDA receptor subunits GRIN2A (Durand et al. 2012) and GRIN2B (Lee et al. 2008), opioid receptors OPRK1 (Chahrour et al. 2008) and OPRM1 (Hwang et al. 2009, Hwang et al. 2010, Samaco et al. 2012), GPRIN1 (Chahrour et al. 2008), MET (Plummer et al. 2013), NOTCH1 (Li et al. 2014). Channels/transporters regulated by MECP2 include TRPC3 (Li et al. 2012) and SLC2A3 (Chen et al. 2013). MECP2 regulates transcription of FKBP5, involved in trafficking of glucocorticoid receptors (Nuber et al. 2005, Urdinguio et al. 2008). MECP2 is implicated in regulation of expression of SEMA3F (semaphorin 3F) in mouse olfactory neurons (Degano et al. 2009). In zebrafish, Mecp2 is implicated in sensory axon guidance by direct stimulation of transcription of Sema5b and Robo2 (Leong et al. 2015). MECP2 may indirectly regulate signaling by neuronal receptor tyrosine kinases by regulating transcription of protein tyrosine phosphatases, PTPN1 (Krishnan et al. 2015) and PTPN4 (Williamson et al. 2015).<p>MECP2 regulates transcription of several transcription factors involved in functioning of the nervous system, such as CREB1, MEF2C, RBFOX1 (Chahrour et al. 2008) and PPARG (Mann et al. 2010, Joss-Moore et al. 2011).<p>MECP2 associates with transcription and chromatin remodeling factors, such as CREB1 (Chahrour et al. 2008, Chen et al. 2013), the HDAC1/2-containing SIN3A co-repressor complex (Nan et al. 1998), and the NCoR/SMRT complex (Lyst et al. 2013, Ebert et al. 2013). There are contradictory reports on the interaction of MECP2 with the SWI/SNF chromatin-remodeling complex (Harikrishnan et al. 2005, Hu et al. 2006). Interaction of MECP2 with the DNA methyltransferase DNMT1 has been reported, with a concomitant increase in enzymatic activity of DNMT1 (Kimura and Shiota 2003).<p>In addition to DNA binding-dependent regulation of gene expression by MECP2, MECP2 may influence gene expression by interaction with components of the DROSHA microprocessor complex and the consequent change in the levels of mature microRNAs (Cheng et al. 2014, Tsujimura et al. 2015).<p>Increased MECP2 promoter methylation is observed in both male and female autism patients (Nagarajan et al. 2008). Regulatory elements that undergo methylation are found in the promoter and the first intron of MECP2 and their methylation was shown to regulate Mecp2 expression in mice (Liyanage et al. 2013). Mouse Mecp2 promoter methylation was shown to be affected by stress (Franklin et al. 2010).<p>The Rett-like phenotype of Mecp2 null mice is reversible (Guy et al. 2007), but appropriate levels of Mecp2 expression need to be achieved (Alvarez-Saavedra et al. 2007). When Mecp2 expression is restored in astrocytes of Mecp2 null mice, amelioration of Rett symptoms occurs, involving non-cell-autonomous positive effect on mutant neurons and increasing level of the excitatory glutamate transporter VGLUT1 (Lioy et al. 2011). Microglia derived from Mecp2 null mice releases higher than normal levels of glutamate, which has toxic effect on neurons. Increased glutamate secretion may be due to increased levels of glutaminase (Gls), involved in glutamate synthesis, and increased levels of connexin-32 (Gjb1), involved in glutamate release, in Mecp2 null microglia (Maezawa and Jin 2010). Targeted deletion of Mecp2 from Sim1-expressing neurons of the mouse hypothalamus recapitulates some Rett syndrome-like features and highlights the role of Mecp2 in feeding behavior and response to stress (Fyffe et al. 2008).<p>Mecp2 overexpression, similar to MECP2 duplication syndrome, causes neurologic phenotype similar to Rett (Collins et al. 2004, Luikenhuis et al. 2004, Van Esch et al. 2005, Alvarez-Saavedra 2007, Van Esch et al. 2012). The phenotype of the mouse model of the MECP2 duplication syndrome in adult mice is reversible when Mecp2 expression levels are corrected (Sztainberg et al. 2015). View original pathway at Reactome.</div>
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The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).
In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
This process is known as lateral inhibition: a molecular mechanism whereby individual cells within a field are stochastically selected to adopt particular cell fates and the NSP inhibits their direct neighbours from doing the same. The NSP has been adopted by several other biological systems for binary cell fate choice. In addition, the NSP is also used during vertebrate segmentation to divide the growing embryo into regular blocks called somites which eventually form the vertebrae. The core of this process relies on regular pulses of Notch signaling generated from a molecular oscillator in the presomatic mesoderm.
The Notch receptor is synthesized in the rough endoplasmic reticulum as a single polypeptide precursor. Newly synthesized Notch receptor is proteolytically cleaved in the trans-golgi network, creating a heterodimeric mature receptor comprising of non-covalently associated extracellular and transmembrane subunits. This assembly travels to the cell surface ready to interact with specific ligands. Following ligand activation and further proteolytic cleavage, an intracellular domain is released and translocates to the nucleus where it regulates gene expression.
Annotated Interactions
Surprisingly, MECP2 deficiency in Rett syndrome results in an overall decreased expression of BDNF (Klein et al. 2007, Chahrour et al. 2008, Fyffe et al. 2008). One proposed mechanism is indirect, through the loss of MECP2-mediated repression of REST and RCOR1 (CoREST) genes, as REST and RCOR1 act as repressors of BDNF transcription from promoter 1 (Abuhatzira et al. 2007). Previously, it was reported that the CoREST complex also represses transcription of Bdnf from the Mecp2-binding murine promoter 4 (corresponding to human MECP2-binding BDNF promoter 3) (Ballas et al. 2005).
For detailed review of dual regulation of BDNF transcription by MECP2, please refer to Li and Pozzo-Miller 2014, and KhorashidAhmad et al. 2016.
Deficit in Bdnf expression in Mecp2 null mice results in downregulation of Igf1 expression through a microRNA-dependent pathway regulated by Bdnf signaling. Induction of signaling by the beta2-adrenegic receptor can restore Igf1 expression in Mecp2 null mice (Mellios et al. 2014).
miR-132 levels increase in response to BDNF signaling in a CREB-dependent way (Vo et al. 2005, Klein et al. 2007, Lyu et al. 2016). In patients with major depressive disorder, miR-132 levels are increased while MECP2 and BDNF levels are decreased (Su et al. 2015).