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dc.contributor.advisorKolodkin, Alex
dc.creatorVissers, Caroline
dc.date.accessioned2020-06-21T20:02:51Z
dc.date.available2020-06-21T20:02:51Z
dc.date.created2020-05
dc.date.issued2019-12-18
dc.date.submittedMay 2020
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/62441
dc.description.abstractChemical modifications on mRNA have recently garnered attention as major regulators of cell behavior in embryonic development and many types of disease. In particular, N6-adenosine (m6A), is an abundant mRNA modification that mediates mRNA fate. Through distinct reader protein binding, m6A promotes various processing events such as mRNA degradation, alternative splicing, nuclear export, and translation initiation. While we have known of the existence of m6A for many years, the recent discovery of m6A demethylases has spurred interest in this dynamic modification as a regulatory system. In vitro work showed that m6A appears to be especially important in stem cell biology, where knockout of the m6A methyltransferase complex components causes major impairments in stem cell self-renewal and differentiation. In vivo work has been severely limited by the fact that full knockout of Mettl3 or Mettl14, which are central parts of the m6A methyltransferase complex, is embryonic lethal. We therefore used conditional knockout mice in which Mettl14 is knocked out in neural stem cells. My thesis has focused on the role of m6A in in vivo brain development, with studies on m6A in mammalian development and Fragile X Syndrome. We showed that m6A promotes mRNA degradation of transcripts that regulate the balance between stem cell self-renewal and neurogenesis. Loss of m6A slows the tempo of neurogenesis and also revealed that neural stem cells are normally pre-patterned with transcription of neural genes prior to differentiation. In parallel, I studied the role of m6A in hypoxic breast cancer cells because hypoxia induces the m6A demethylase, ALKBH5, to drive global changes in m6A methylation patterns. In this system, m6A promotes translation of modified transcripts to promote global translation, cell division, and oxidative metabolism. The study of m6A in multiple systems reveals the incredible cell-type specificity and dynamic nature of m6A.
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.publisherJohns Hopkins University
dc.subjectepitranscriptome
dc.subjectepigenetics
dc.subjectneurogenesis
dc.titlem6A mRNA METHYLATION IN DEVELOPMENT AND DISEASE
dc.typeThesis
thesis.degree.disciplineNeuroscience
thesis.degree.grantorJohns Hopkins University
thesis.degree.grantorSchool of Medicine
thesis.degree.levelDoctoral
thesis.degree.namePh.D.
dc.date.updated2020-06-21T20:02:51Z
dc.type.materialtext
thesis.degree.departmentNeuroscience
dc.contributor.committeeMemberSong, Hongjun
dc.contributor.committeeMemberWatanabe, Shigeki
dc.contributor.committeeMemberSemenza, Gregg
dc.publisher.countryUSA
dc.creator.orcid0000-0002-9888-8516


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