Regulation of MECP2 expression and activity

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Homo sapiens
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Transcription of the MECP2 gene is known to be regulated by methylation of the promoter and the first intron, but the responsible methyltransferases are not known (Nagarajan et al. 2008, Franklin et al. 2010, Liyanage et al. 2013).

Translation of MECP2 mRNA is negatively regulated by the microRNA miR-132. Transcription of miR-132 is regulated by BDNF signaling, through an unknown mechanism (Klein et al. 2007, Su et al. 2015).

Binding of MECP2 to other proteins and to DNA is regulated by posttranslational modifications, of which phosphorylation has been best studied. Calcium dependent protein kinases, PKA and CaMK IV, activated by neuronal membrane depolarization, phosphorylate MECP2 at threonine residue T308 (corresponding to T320 in the longer MECP2 splicing isoform, MECP2_e1). Phosphorylation at T308 correlates with neuronal activity and inhibits binding of MECP2 to the nuclear receptor co-repressor complex (NCoR/SMRT) (Ebert et al. 2013). In resting neurons, MECP2 is phosphorylated at serine residue S80, which results in a decreased association of MECP2 with chromatin. Nuclear serine/threonine protein kinase HIPK2 phosphorylates MECP2 on serine residue S80 (Bracaglia et al. 2009). In activity-induced neurons, upon neuronal membrane depolarization, MECP2 S80 becomes dephosphorylated, and MECP2 acquires phosphorylation on serine S423 (corresponding to mouse Mecp2 serine S421). CaMK IV is one of the kinases that can phosphorylate MECP2 on S423. Phosphorylation of MECP2 at S423 increases MECP2 binding to chromatin (Zhou et al. 2006, Tao et al. 2009, Qiu et al. 2012). AURKB phosphorylates MECP2 at serine residue S423 in dividing adult neuronal progenitor cells (Li et al. 2014).

Besides binding to the NCoR/SMRT co-repressor complex (Lyst et al. 2013, Ebert et al. 2013), MECP2 binds the SIN3A co-repressor complex. This interaction involves the transcriptional repressor domain of MECP2 and the amino terminal part of the HDAC interaction domain (HID) of SIN3A. HDAC1 and HDAC2 are part of the SIN3A co-repressor complex that co-immunoprecipitates with MECP2 (Nan et al. 1998). While binding of MECP2 to SIN3A at target genes is associated with transcriptional repression, binding to CREB1 at target genes is associated with transcriptional activation (Chahrour et al. 2008, Chen et al. 2013). Function of MECP2 can be affected by binding to FOXG1, another gene mutated in Rett syndrome besides MECP2 and CDKL5 (Dastidar et al. 2012), and HTT (Huntingtin) (McFarland et al. 2013). The subnuclear localization of MECP2 may be affected by binding to the Lamin B receptor (LBR) (Guarda et al. 2009).

Literature References
PubMed ID Title Journal Year
23770565 Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor

de Lima Alves, F, Kastan, NR, Guy, J, Greenberg, ME, Ekiert, R, Bird, A, Selfridge, J, Nowak, J, Ebert, DH, Robinson, ND, Merusi, C, Lyst, MJ, Rappsilber, J

Nat. Neurosci. 2013
24105466 MeCP2: a novel Huntingtin interactor

Huizenga, MN, Sangrey, GR, Darnell, SB, Cha, JH, Sadri-Vakili, G, McFarland, KN, Outeiro, TF, Berezovska, O

Hum. Mol. Genet. 2014
17994015 Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA

Impey, S, Mandel, G, Lioy, DT, Klein, ME, Goodman, RH, Ma, L

Nat. Neurosci. 2007
19132145 MECP2 promoter methylation and X chromosome inactivation in autism

Patzel, KA, Hansen, RL, Jiang, R, Van de Water, J, Swanberg, SE, Robinson, WP, LaSalle, JM, Pessah, IN, Hertz-Picciotto, I, Martin, M, Nagarajan, RP, Yasui, DH

Autism Res 2008
22262897 The Rett syndrome protein MeCP2 regulates synaptic scaling

Ghosh, A, Qiu, Z, Zhang, Y, Liu, XY, Lieberman, DN, Sylwestrak, EL

J. Neurosci. 2012
26239616 MeCP2 controls hippocampal brain-derived neurotrophic factor expression via homeostatic interactions with microRNA‑132 in rats with depression

Zhao, Y, Su, M, Hong, J, Liu, S, Xue, X

Mol Med Rep 2015
19225110 Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function

Sun, YE, Klose, RJ, Wu, H, Jaenisch, R, Tao, J, Sherman, NE, Martinowich, K, Schanen, C, Wang, W, Chang, Q, Hu, K

Proc. Natl. Acad. Sci. U.S.A. 2009
19820693 Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis

Greenberg, ME, Conca, B, Kilstrup-Nielsen, C, Landsberger, N, Bergo, A, Soddu, S, Rusconi, L, Bracaglia, G, Zhou, Z

EMBO Rep. 2009
20673872 Epigenetic transmission of the impact of early stress across generations

Linder, N, Russig, H, Vizi, S, Weiss, IC, Michalon, A, Franklin, TB, Gräff, J, Mansuy, IM

Biol. Psychiatry 2010
23493374 Creb1-Mecp2-(m)CpG complex transactivates postnatal murine neuronal glucose transporter isoform 3 expression

Thamotharan, S, Chen, Y, Devaskar, SU, Shin, BC

Endocrinology 2013
24238559 Decitabine alters the expression of Mecp2 isoforms via dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells

Zachariah, RM, Liyanage, VR, Rastegar, M

Mol Autism 2013
25420914 Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signalling pathway

Zhong, X, Jin, P, Chau, KF, Masliah, J, Kong, G, Chi, J, Santistevan, NJ, Kadakia, M, Zhang, J, Guo, W, Li, H, Li, X, Chang, Q, Zhao, X

Nat Commun 2014
19331822 Interaction between the inner nuclear membrane lamin B receptor and the heterochromatic methyl binding protein, MeCP2

Bolognese, F, Guarda, A, Badaracco, G, Bonapace, IM

Exp. Cell Res. 2009
18511691 MeCP2, a key contributor to neurological disease, activates and represses transcription

Qin, J, Jung, SY, Wong, ST, Zoghbi, HY, Shaw, C, Chahrour, M, Zhou, X

Science 2008
22357867 Isoform-specific toxicity of Mecp2 in postmitotic neurons: suppression of neurotoxicity by FoxG1

Narayanan, V, Verma, P, D'Mello, SR, Ma, C, Rawat, V, Dastidar, SG, Bardai, FH, Price, V

J. Neurosci. 2012
17046689 Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation

Greenberg, ME, Griffith, EC, Ho, HY, Steen, JA, Lin, Y, Hu, L, Chen, WG, Zhao, WN, Cohen, S, Hong, EJ, Savner, E, Schmidt, L, Weitz, CJ, Zhou, Z

Neuron 2006
23770587 Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR

Kastan, NR, Greenberg, ME, Ekiert, R, Bird, AP, Lyst, MJ, Hu, LS, Gabel, HW, Cohen, S, Navarro, AJ, Ebert, DH, Robinson, ND

Nature 2013
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