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dc.contributor.advisorIssa, Jean-Pierre
dc.creatorMadireddi, Priyanka
dc.date.accessioned2020-10-27T15:14:20Z
dc.date.available2020-10-27T15:14:20Z
dc.date.issued2015
dc.identifier.other965642562
dc.identifier.urihttp://hdl.handle.net/20.500.12613/1806
dc.description.abstractHigh level DNA methylation of promoter CpG islands (CGIs) represses gene expression. However, low-level CGI methylation is currently not distinguished from complete absence of methylation in the literature. Here we show that very low levels of methylation or methylation seeds (1-20%) on promoter CGIs is present in 5-20% of human genes and negatively correlates with gene expression in all tissues examined. In vitro, seeding directly represses reporter gene expression, an effect mediated by methyl-CpG-binding proteins as transient knockdown of MBD4 reverses this repression. In vivo, seeded genes are enriched for polycomb occupancy but seeding can also occur in H3K4me3 occupied promoters, where it also correlates with gene repression independently of Polycomb repressive complex binding. Seeded CGIs in normal WBCs are 19 fold and 65 fold more likely to gain hypermethylation in Acute Myelogenous Leukemia and Myelodysplastic Syndrome patients respectively, compared to unmethylated CGIs (i.e. those with <1% methylation). This study reveals a novel epigenetic mechanism of tissue specific methylation seeds that have strong effects on gene expression in healthy tissues, possess unique histone status, and predispose to gain of methylation in leukemias more so than previously known factors. In the second part, we analyzed the role of chromodomain protein CHD7 in CpG island methylator phenotype (CIMP) Colorectal Cancers (CRCs). Analysis of CHD7 target genes identified that frequently methylated genes in CIMP-positive CRCs have significantly higher enrichment of CHD7 occupancy in mouse neural stem cells and are among genes regulated by CHD7 in mouse embryonic stem cells. This study provides evidence for a causal link between CHD7 mutations in CRCs and the CIMP phenotype.
dc.format.extent138 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectBiology, Molecular
dc.subjectGenetics
dc.titleTHE ROLE OF CIS- AND TRANS-ACTING FACTORS IN REGULATION OF DNA METHYLATION
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberSapienza, Carmen
dc.contributor.committeememberLiebermann, Dan A.
dc.contributor.committeememberEngel, Nora
dc.contributor.committeememberBellacosa, Alfonso
dc.description.departmentMolecular Biology and Genetics
dc.relation.doihttp://dx.doi.org/10.34944/dspace/1788
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-10-27T15:14:20Z


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