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