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METTL3 Dependent M6A Regulates Chromatin Modifiers in Epithelial Development / Alexandra Marie Maldonado Lopez.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Maldonado Lopez, Alexandra Marie, author.
- Language:
- English
- Subjects (All):
- Genetics.
- Cellular biology.
- Molecular biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Genetics.
- Cellular biology.
- Molecular biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (109 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- N6-methyladenosine (m6A) is the most abundant modification on mammalian messenger RNAs (mRNAs). It is catalyzed co-transcriptionally by methyltransferase-like protein 3 (METTL3), which is part of the METTL3-METTL14 writer complex. To understand the role of m6A in a self-renewing epithelial tissue, we deleted Mettl3 in epidermal progenitors in vivo (Mettl3-eKO). Mettl3-eKO mice present dysfunctional development and self-renewal of the epidermis and non-lingual epithelium, which includes loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations. We show that METTL3 promotes the m6A-mediated instability and degradation of mRNAs of critical histone modifying enzymes. Depletion of METTL3 results in the loss of m6A on these chromatin modifying transcripts, thus increasing their mRNA abundance, protein expression and associated modifications. This upregulation in epigenetic writers results in widespread gene expression abnormalities that lead to the gross phenotypic abnormalities in the epidermis and tongue. Altogether, these results identified an additional layer of gene regulation within epithelial tissues, revealing an essential role for m6A in the regulation of chromatin modifiers (a crosstalk between epitranscriptomics and epigenetics), and highlighting a critical role for METTL3-catalyzed m6A in proper epithelial development and self-renewal that lays the foundation for novel clinical approaches to maintain skin homeostasis and treat benign and malignant skin diseases.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Capell, Brian C.; Committee members: Hamilton, Kathryn E.; Liu, Fange Kathy; Lin, Lan; Seykora, John T.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381471779
- Access Restriction:
- Restricted for use by site license.
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