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Maintenance of germ line and somatic DNA methylation during mouse development

Reinhart, Bonnie Lynn (2003) Maintenance of germ line and somatic DNA methylation during mouse development. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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DNA methylation in mammals is involved in several essential processes including X chromosome inactivation, genomic imprinting, and host defense against mobile genetic elements. How methylation is targeted to specific sequences in the germ line and how specific methylation patterns are maintained during development is not fully understood. Genomic methylation is established in the gamete, decreases dramatically during preimplantation development, and is re-established after implantation of the blastocyst. However, the methylation present at imprinted loci is specifically maintained during preimplantation development. Imprinted genes are located in clusters, and within each gene cluster parent-of-origin specific expression is governed by an imprinting center (IC). The ICs of the maternally imprinted murine Snrpn, Kcnq1, and Igf2r gene clusters coincide with their differentially methylated domains (DMDs). We have shown that specific DMD sequences are required to establish differential methylation at an imprinted locus. Hybrid transgenes were generated using a non-imprinted derivative of the imprinted RSVIgmyc mouse transgene, Ig/myc, and sequences from endogenous imprinted gene DMDs. Addition of specific DMD sequences to the Ig/myc transgene restored its imprinting. Only the tandem repeats found within the Snrpn, Kcnq1, and Igf2r DMDs were capable of establishing maternal-specific transgene methylation. These experiments have also shown that the methylation on imprinted gene DMD sequences is specifically maintained during the early stages of preimplantation development. These results clearly demonstrate the importance of tandem repeats in the process of genomic imprinting. DNA methylation is also critical for silencing intracisternal A particle (IAP) transposition within the genome. It is thought that maintenance of IAP element methylation during preimplantation is critical to repress IAP element transcription and transposition. The methylation of IAP element long terminal repeat (LTR) sequences was analyzed at the blastocyst stage of preimplantation development using the bisulfite genomic sequencing technique. These experiments have shown that methylation is maintained on the majority of IAP elements at the blastocyst stage of preimplantation development. However, the methylation on specific IAP elements is completely lost at this time, including the methylation of single IAP element LTRs.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Reinhart, Bonnie Lynnbreinhar@pitt.eduBREINHAR
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairChaillet, J. Richardchaillet@pitt.eduCHAILLET
Committee CoChairChapman, Deborahdlc7@pitt.eduDLC7
Committee MemberHomanics, Gregg
Committee MemberHildebrand, Jeffreyjeffh@pitt.eduJEFFH
Committee MemberArndt, Karenarndt@pitt.eduARNDT
Date: 17 November 2003
Date Type: Completion
Defense Date: 18 August 2003
Approval Date: 17 November 2003
Submission Date: 21 August 2003
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: IAP elments; mouse; trinucleotide repeats
Other ID:, etd-08212003-145414
Date Deposited: 10 Nov 2011 20:00
Last Modified: 15 Nov 2016 13:49


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