the role of methyl-cpg binding protein 2 in rett syndrome jessica connor
DESCRIPTION
Rett syndrome is caused by mutations in the MECP2 gene Bird, A. Biochem. Soc. Trans. (2008) 36, 575–583TRANSCRIPT
The role of The role of Methyl-CpG Binding Methyl-CpG Binding
Protein 2 Protein 2 in Rett Syndromein Rett Syndrome
Jessica Connor
http://www.nih.gov/news/research_matters/june2008/06092008rett.htm
Rett Syndrome is a neurodevelopmental
disorderHypotonia – loss of muscle tone
Apraxia —inability to perform motor functions
• loss of use hands• repetitive hand movements• diminished eye contact• gait abnormalities• lack of speech development
Other Symptoms• autism like
behaviors• toe walking• sleep problems• cognitive disabilities• seizures• breathing problems• teeth grinding• difficulty chewing
http://www.youtube.com/watch?v=rQvTgV7f2JM
Rett syndrome is caused by mutations in the MECP2
gene
Bird, A. Biochem. Soc. Trans. (2008) 36, 575–583
http://ghr.nlm.nih.gov/dynamicImages/chromomap/mecp2.jpeg
MECP2 GO Terms Suggest Function
Biological Process• Negative regulation of transcription from RNA
polymerase II promoterCellular Component• Mitochondrion• Nucleolus• Nucleus *Also noted in Uniprot Molecular Function• DNA binding • Double stranded methylated DNA binding• Protein binding • Transcription corepressor activity
MECP2 Mouse GO Terms Shed More Light on Role in Rett
SyndromeBehavior adult locamotory behaviorresponse to hypoxiasocial behaviorNeurologicalbrain developmentcerebellum developmentdendrite developmentlong term synaptic potentiationnegative regulation of neuron
apoptosisneurite development neuromuscular process controlling
postureneuron differentiationneuron maturationsynaptic transmissionsynaptogenesis
Transcriptionnegative regulation of transcription, DNA dependent positive regulation
of transcription, DNA dependentregulation of transcriptionEpigenetics chromatin silencinggenetic imprintinghistone acetylationhistone methylationregulation of gene expression,
epigeneticOthercatecholamine secretion (hormonecontrolling fight or flight response)respiratory gaseous exchange
The MECP2 gene encodes the MECP2 protein
SMART
Protein Data Bank
MECP2 homologs are found in other mammals
Phylogeny.fr
MECP2 domains are well conserved in homologs
Homo sapiens…………......
Pan troglodytes……………
Canis lupus familiaris …….
Bos taurus…………………
Rattus norvegicus…………
Mus musculus……………..
Danio rerio…………………
SMART
The MECP2 protein represses transcription of
methylated genes
http://www.germaco.net/intro_rett_gb.html
MECP2 interacts with proteins that form the histone
deacetylase complex and other transcription factors
Pan troglodytes Mus musculus
Danio rerio
Sin3A
Gene Therapy Experiments
• Developed mouse model with silenced MECP2 that can be activated with injections of Tamoxifen
• Mice initially had Rett Syndrome phenotype• After MECP2 was activated, symptoms
disappeared• Rett syndrome symptoms are not
irreversible• Not a direct therapeutic approach
Future Directions• Determine which genes are
abnormally expressed in Rett Syndrome– Gel shift to determine which genes bind
to MECP2. Use microarray to look at expression changes in these genes in the presence and absence of MECP2
– Mass Spec analysis of brain tissue in MECP2 null mice vs. WT mice