MECP2
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MECP2 (methyl CpG binding protein 2) is a
MECP2 is an important reader of DNA methylation. Its methyl-CpG-binding (MBD) domain recognizes and binds
Function
MECP2 protein is found in all cells in the body, including the brain, acting as a transcriptional repressor and activator, depending on the context. However, the idea that MECP2 functions as an activator is relatively new and remains controversial.[10] In the brain, it is found in high concentrations in neurons and is associated with maturation of the central nervous system (CNS) and in forming synaptic contacts.[11]
Mechanism of action
The MeCP2 protein binds to forms of
Once bound, MeCP2 will condense the
Reduced expression of MECP2 in Mecp2+/- neural stem cells causes an increase in senescence, impairment of proliferative capacity and accumulation of unrepaired DNA damage.[16] After treatment of Mecp2+/- cells with any of three different DNA damaging agents, the cells accumulated more damaged DNA and were more prone to cell death than control cells.[16] It was concluded that reduced MECP2 expression causes reduced capacity to repair DNA and this likely contributes to neurological decline.[16]
Structure
MECP2 is part of a family of methyl-CpG-binding domain proteins (MBD), but possesses its own unique differences which help set it apart from the group. It has two functional domains:
- a methyl-cytosine-binding domain (MBD) composed of 85 amino acids; and
- a transcriptional repression domain (TRD) composed of 104 amino acids
The MBD domain forms a wedge and attaches to the methylated CpG sites on the DNA strands. The TRD region then reacts with SIN3A to recruit histone deacetylases (HDAC).[17] There are also unusual, repetitive sequences found at the carboxyl terminus. This region is closely related to the fork head family, at the amino acid level.[18]
Role in disease
The role of MECP2 in disease is primarily associated with either a loss of function (under expression) of the MECP2 gene as in
Mutations in the MECP2 gene have also been identified in people with several other disorders affecting the central nervous system. For example, MECP2 mutations are associated with some cases of moderate to severe X-linked mental retardation. Mutations in the gene have also been found in males with severe brain dysfunction (
More recent studies reported genetic polymorphisms in the MeCP2 genes in patients with
The genetic loss of MECP2 has been identified as changing the properties of cells in the
Researchers have concluded that "Because these neurons are a pivotal source of norepinephrine throughout the brainstem and forebrain and are involved in the regulation of diverse functions disrupted in Rett syndrome, such as respiration and cognition, we hypothesize that the locus ceruleus is a critical site at which loss of MECP2 results in CNS dysfunction."[23]
Interactive pathway map
Click on genes, proteins and metabolites below to visit related articles. [§ 1]
Interactions
MECP2 has been shown to
MeCP2 and Hormones
MeCP2 in the developing rat brain regulates important social development in a sexually dimorphic manner. MeCP2 levels are different between males and females in the developing rat brain 24 hours after birth within the amygdala and hypothalamus, but this difference is no longer observed 10 days after birth. Specifically, males express less MeCP2 than females,[26] and this aligns with the steroid-sensitive time period of the neonatal rat brain. Reductions in MeCP2 with Small interfering RNA (siRNA) during the first few days of life reduce male levels of juvenile social play behavior to female typical levels, but do not affect female juvenile play behavior.[27]
MeCP2 is important in organizing hormone-related behaviors and sex differences in the developing rat amygdala. MeCP2 appears to regulate
Early life stress
MeCP2 monitors the response to early life stress. Early life stress is correlated with hyper-phosphorylation of the MeCP2 protein in
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000169057 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031393 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 3350350.
- S2CID 6825994.
- PMID 18511691.
- ^ "Entrez Gene: MECP2 methyl CpG binding protein 2 (Rett syndrome)".
- PMID 31819097.
- ^ PMID 18511680.
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- PMID 18511691.
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- ^ PMID 29563495.
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- S2CID 37525856. Archived from the original(PDF) on 2007-08-14.
- PMID 15809268.
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- ^ Hunt, Katie (12 January 2016). "Chinese scientists create monkeys with autism gene". CNN News. Retrieved 2016-01-27.
- PMID 18320046.
- ^ PMID 19793977.
- ^ PMID 11441023.
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- S2CID 3328884.
Further reading
- Chahrour M, Zoghbi HY (2007). "The story of Rett syndrome: from clinic to neurobiology". Neuron. 56 (3): 422–37. S2CID 16266882.
- Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML, Vance JM, Pericak-Vance MA (2003). "Identification of MeCP2 mutations in a series of females with autistic disorder". Pediatr Neurol. 28 (3): 205–11. PMID 12770674.
- Kerr AM, Ravine D (2003). "Review article: breaking new ground with Rett syndrome". J Intellect Disabil Res. 47 (Pt 8): 580–7. PMID 14641805.
- Neul JL, Zoghbi HY (2004). "Rett syndrome: a prototypical neurodevelopmental disorder". Neuroscientist. 10 (2): 118–28. S2CID 9617631.
- Schanen C, Houwink EJ, Dorrani N, Lane J, Everett R, Feng A, Cantor RM, Percy A (2004). "Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome". Am J Med Genet A. 126 (2): 129–40. S2CID 32897044.
- Van den Veyver IB, Zoghbi HY (2001). "Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome". Brain Dev. 23 (Suppl 1): S147–51. S2CID 26138178.
- Webb T, Latif F (2001). "Rett syndrome and the MECP2 gene". J Med Genet. 38 (4): 217–23. PMID 11283201.
- Shahbazian MD, Zoghbi HY (2003). "Rett syndrome and MeCP2: linking epigenetics and neuronal function". Am. J. Hum. Genet. 71 (6): 1259–72. PMID 12442230.
- Moog U, Smeets EE, van Roozendaal KE, et al. (2003). "Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2)". Eur. J. Paediatr. Neurol. 7 (1): 5–12. PMID 12615169.
- Miltenberger-Miltenyi G, Laccone F (2004). "Mutations and polymorphisms in the human methyl CpG-binding protein MECP2". Hum. Mutat. 22 (2): 107–15. S2CID 42516576.
- Weaving LS, Ellaway CJ, Gécz J, Christodoulou J (2006). "Rett syndrome: clinical review and genetic update". J. Med. Genet. 42 (1): 1–7. PMID 15635068.
- Bapat S, Galande S (2005). "Association by guilt: identification of DLX5 as a target for MeCP2 provides a molecular link between genomic imprinting and Rett syndrome". BioEssays. 27 (7): 676–80. PMID 15954098.
- Zlatanova J (2005). "MeCP2: the chromatin connection and beyond". Biochem. Cell Biol. 83 (3): 251–62. PMID 15959553.
- Kaufmann WE, Johnston MV, Blue ME (2006). "MeCP2 expression and function during brain development: implications for Rett syndrome's pathogenesis and clinical evolution". Brain Dev. 27 (Suppl 1): S77–S87. S2CID 702975.
- Armstrong DD (2006). "Can we relate MeCP2 deficiency to the structural and chemical abnormalities in the Rett brain?". Brain Dev. 27 (Suppl 1): S72–S76. S2CID 45587850.
- Santos M, Coelho PA, Maciel P (2006). "Chromatin remodeling and neuronal function: exciting links". PMID 16681803.
- Bienvenu T, Chelly J (2006). "Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized". Nature Reviews Genetics. 7 (6): 415–26. S2CID 28215286.
- Francke U (2007). "Mechanisms of disease: neurogenetics of MeCP2 deficiency". Nature Clinical Practice Neurology. 2 (4): 212–21. S2CID 22710951.
External links
- International Rett Syndrome Foundation
- Rett UK Support and Research Charity
- Reverse Rett UK
- Rett Registry UK
- Rett Syndrome Research Trust
- GeneCard
- RettBASE: IRSA MECP2 Variation Database
- GeneReview/NIH/UW entry on MECP2-Related Disorders
- GeneReviews/NCBI/NIH/UW entry on MECP2 Duplication Syndrome
- UK Site for Families Affected by MECP2.
- Site for Families Affected by MECP2.
- Site officiel français sur la duplication MeCP2
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