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Review
. 2023 Feb 20;24(4):4218.
doi: 10.3390/ijms24044218.

MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism

Yen My Vuu  1 , Chris-Tiann Roberts  1 , Mojgan Rastegar  1
Affiliations
Review

MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism

Yen My Vuu et al. Int J Mol Sci. .

Abstract

DNA methylation, one of the most well-studied epigenetic modifications, is involved in a wide spectrum of biological processes. Epigenetic mechanisms control cellular morphology and function. Such regulatory mechanisms involve histone modifications, chromatin remodeling, DNA methylation, non-coding regulatory RNA molecules, and RNA modifications. One of the most well-studied epigenetic modifications is DNA methylation that plays key roles in development, health, and disease. Our brain is probably the most complex part of our body, with a high level of DNA methylation. A key protein that binds to different types of methylated DNA in the brain is the methyl-CpG binding protein 2 (MeCP2). MeCP2 acts in a dose-dependent manner and its abnormally high or low expression level, deregulation, and/or genetic mutations lead to neurodevelopmental disorders and aberrant brain function. Recently, some of MeCP2-associated neurodevelopmental disorders have emerged as neurometabolic disorders, suggesting a role for MeCP2 in brain metabolism. Of note, MECP2 loss-of-function mutation in Rett Syndrome is reported to cause impairment of glucose and cholesterol metabolism in human patients and/or mouse models of disease. The purpose of this review is to outline the metabolic abnormalities in MeCP2-associated neurodevelopmental disorders that currently have no available cure. We aim to provide an updated overview into the role of metabolic defects associated with MeCP2-mediated cellular function for consideration of future therapeutic strategies.

Keywords: AMPK; BDNF; DNA methylation; MeCP2 isoforms; Rett Syndrome; autophagy; brain development; brain metabolism; cholesterol; epigenetics; glucose; mTOR.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram of (A) MECP2/Mecp2 gene, (B) MECP2E1 and MECP2E2 transcripts, (C) MeCP2E1 and MeCP2E2 isoforms. MeCP2: methyl-CpG binding protein 2. The dark yellow boxes show 5′ and 3′ untranslated regions (UTR). The drawing is not to scale. Information obtained from [12,74,75,77]. Figure is created with BioRender.com.
Figure 2
Figure 2
The role of MeCP2 in transcriptional regulation. (A) Upon binding to methylated CpG di-nucleotides (5mC), MeCP2 recruits repressor complexes such as mSIN3A, HDACs, and NCoR-SMRT to suppress gene transcription. (B) Upon binding to 5hmC, MeCP2 interacts with CREB to promote transcriptional activation and recruitment of other activators. (C) DNMTs add methyl groups onto the fifth carbon of cytosine residues in the CpG di-nucleotides to form 5mC, whereas TET enzymes oxidize the methyl groups to form 5hmC. 5hmC: 5-hydroxymethylcytosine; 5mC: 5-methylcytosine; CREB: cAMP response element binding protein; DNMTs: DNA methyltransferases; HDACs: histone deacetylases; mSIN3A: mammalian switch-independent 3A; MeCP2: methyl-CpG binding protein 2; NCoR: nuclear receptor corepressor; SMRT: silencing mediator for retinoid and thyroid hormone receptors; TET: ten–eleven translocation. Information obtained from [13,15,53,54,64,87,92,93,94]. Figure is created with BioRender.com.
Figure 3
Figure 3
Key roles of glucose and cholesterol in the brain. Glucose enters the brain through the blood-brain barrier (BBB) and is subsequently involved in ATP production, neurotransmitter homeostasis and autophagy activity. In the adult brain, cholesterol is mainly synthesized in the astrocytes and then delivered to neurons by transporter “ApoE”. In the brain, cholesterol greatly contributes to myelination, synaptic formation, and regulates autophagy. ApoE: apolipoprotein B; ATP: adenosine triphosphate; BBB: blood-brain barrier. GABA: gamma amino butyric acid. Information obtained from [119,121,122,123,124,125,126,127,128,129,130,131,132]. Figure is created with BioRender.com.
Figure 4
Figure 4
The potential links between MeCP2 with glucose and cholesterol metabolism. Brain-derived neurotrophic factor (BDNF), a downstream target of MeCP2, is engaged in both glucose and cholesterol metabolism; similar to mTORC1 and AMPK signaling pathways. Moreover, MeCP2 may regulate the expression of CYP46A1, which is a key factor in brain cholesterol homeostasis. MeCP2 promotes expression of GLUT3, which is a crucial transporter of glucose to neurons. ABCA1: ATP binding cassette subfamily A member 1; ACC1: acetyl-CoA carboxylase 1; AMPK: adenosine 5′-monophosphate activated protein kinase; AS160: Akt substrate of 160 kDa; BDNF: brain-derived neurotrophic factor; CREB1: cAMP response element-binding protein 1; CYP46A1: cytochrome P450 family 46 subfamily A member 1; G6PD: glucose-6-phosphate dehydrogenase; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GLUT3: glucose transporter 3; GLUT4: glucose transporter 4; HIF1α: hypoxia-inducible factor 1-alpha; HMGCR: 3-hydroxy-3-methyl-glutaryl-CoA reductase; MeCP2: methyl-CpG Binding Protein 2, mTORC1: mechanistic target of rapamycin complex 1; PGC-1α: peroxisome-proliferator-activated receptor gamma coactivator 1 alpha; PKM2: pyruvate kinase M2; PPARγ: peroxisome proliferator-activated receptor gamma; PTP1B: protein tyrosine phosphatase 1B; SREBP: sterol regulatory element-binding protein, TRKB: tropomyosin receptor kinase B. Information obtained from [18,150,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183]. Please note that the molecular signaling cascades showing the link between MeCP2 and glucose metabolism as well as cholesterol metabolism were taken from different organs and cell type-specific regulation. Figure is created with BioRender.com.
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References

    1. Liyanage V.R.B., Zachariah R.M., Delcuve G.P., Davie J.R., Rastegar M. Chromatin Structure and Epigenetics. In: Urbano K.V., editor. Advances in Genetics Research. Volume 13. Nova Science Publishers; Hauppauge, NY, USA: 2015. pp. 57–88.
    1. Delcuve G.P., Rastegar M., Davie J.R. Epigenetic control. J. Cell. Physiol. 2009;219:243–250. doi: 10.1002/jcp.21678. - DOI - PubMed
    1. Spadafora C. The epigenetic basis of evolution. Prog. Biophys. Mol. Biol. 2023 doi: 10.1016/j.pbiomolbio.2023.01.005. - DOI - PubMed
    1. Cheema M.S., Ausio J. The Structural Determinants behind the Epigenetic Role of Histone Variants. Genes. 2015;6:685–713. doi: 10.3390/genes6030685. - DOI - PMC - PubMed
    1. Liyanage V.R., Jarmasz J.S., Murugeshan N., Del Bigio M.R., Rastegar M., Davie J.R. DNA modifications: Function and applications in normal and disease States. Biology. 2014;3:670–723. doi: 10.3390/biology3040670. - DOI - PMC - PubMed

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