Koppes, Erik
(2016)
The Role of Genomic Imprints in Placental Biology.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Genomic imprinting is a process by which heritable epigenetic marks at a subset of genomic loci are established in a sex-specific manner in parental gametes and then maintained in nascent offspring. This study probes the poorly understood function of genomic imprints in placental biology. Genomic imprints are responsible for the regulation of parent-of-origin specific monoallelic expression of clusters of imprinted genes. The primary epigenetic mark that distinguishes parental alleles at imprinted loci is 5-methylcytosine in the context of cytosine-guanine (CpG) dinucleotides within differentially methylated domains (DMDs). The Dnmt1 gene encodes the maintenance DNA methyltransferase, an enzyme responsible for replicating CpG methylation that is critical throughout the process of genomic imprinting. Genetic disruption of the oocyte specific isoform of Dnmt1 (Dnmt1o) results in partial and wide-spread loss of DMD methylation during preimplantation development and has strong effects on embryonic and extraembryonic development. In this dissertation the morphology of DNMT1o-deficient placentas is examined and their abnormal phenotypes correlated with loss of methylation at specific DMDs. A strong association between loss of methylation at the Kcnq1 DMD and accumulation of trophoblast giant cells was made. In addition, an association between loss of methylation at the Peg10 DMD and loss of fetal viability and placental labyrinthine volume was made. In conjunction with my study of the Dnmt1Δ1o model, I have engineered a novel targeted deletion of the imprinted Klf14 gene and found it has an effect on placental growth. My thesis unambiguously shows that genomic imprints are essential for placental development.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
20 May 2016 |
| Date Type: |
Publication |
| Defense Date: |
19 April 2016 |
| Approval Date: |
20 May 2016 |
| Submission Date: |
3 May 2016 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
293 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Integrative Molecular Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Genomic Imprints, Genomic Imprinting, Placenta, Mouse, DNMT1, DNA methylation, Peg10, Kcnq1, Mest, Klf14, preimplantation, spongiotrophoblast, labyrinth, |
| Date Deposited: |
20 May 2016 15:15 |
| Last Modified: |
19 Dec 2016 14:43 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/28048 |
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