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dc.contributor.advisorBird, Adrian
dc.contributor.advisorCook, Atlanta
dc.contributor.authorTillotson, Anne Rebekah
dc.date.accessioned2018-03-22T11:25:48Z
dc.date.available2018-03-22T11:25:48Z
dc.date.issued2017-07-07
dc.identifier.urihttp://hdl.handle.net/1842/28917
dc.description.abstractMeCP2 was identified by its ability to bind DNA in a methylation-specific manner. Yet, how it interprets the DNA methylome remains unclear. Several mechanisms have been proposed, including a role in transcriptional repression. MeCP2 is highly abundant in the brain, and loss-of-function mutations result in a neurological disorder called Rett syndrome (RTT). Strikingly, RTT-causing missense mutations are almost all located in either the methyl-CpG-binding domain (MBD) or a region that has been shown to bind the NCoR/SMRT co-repressor complex (NID). This suggests that the MBD and the NID are the key functional domains in MeCP2, and that the role of MeCP2 is to form a ‘bridge’ between chromatin and the co-repressor complex to regulate gene expression. To test this ‘bridge’ hypothesis, I have made an allelic series of knock-in mice with truncated forms of MeCP2 to determine whether the other regions are dispensable for protein function. The three other regions of MeCP2 (the N-terminus before the MBD, the Intervening region between the MBD and the NID, and the C-terminus after the NID) were deleted in a step-wise manner to produce progressively smaller truncated proteins. Knock-in mice which lack just the N-terminus or both the N- and C-termini are phenotypically normal. Therefore, these regions, which together make up 46% of the protein sequence, are dispensable for MeCP2 function in vivo. Additional deletion of the Intervening region, retaining only 34% of the original sequence, results in mild RTT-like symptoms in the knock in mice. This is likely to be caused by this protein’s decreased stability and reduced ability to bind the NCoR/SMRT complex in the brain. The most severely truncated protein is nevertheless able to reverse the Mecp2-null phenotype when reactivated after the onset of symptoms. Together, these findings strongly support the ‘bridge’ hypothesis.en
dc.contributor.sponsorBiotechnology and Biological Sciences Research Council (BBSRC)en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.subjectMeCP2en
dc.subjectepigeneticen
dc.subjectmouse modelen
dc.subjectgene expressionen
dc.titleIdentifying the key functions of MeCP2 via genetic manipulation in miceen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2018-07-07
dcterms.accessRightsRestricted Accessen


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