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Temple University

1. Korostowski, Lisa. Transcript Regulation within the Kcnq1 Domain.

Degree: PhD, 2012, Temple University

Molecular Biology and Genetics

Epigenetics was a term first coined to understand how cells with the same genetic make up can differentiate into various cell types. Elegant research over the past 30 years has shown that these mechanisms include heritable marks such as DNA methylation and histone modifications along with stable expression of non- coding RNAs. Within the realm of epigenetics is a phenomenon known as genomic imprinting. Imprints are marks that distinguish the maternal from the paternal chromosomes in the form of methylation. Methylation marks can influence transcript expression, resulting in only one allele being expressed. One imprinted domain is the Kcnq1 domain located on chromosome 11p15.5 in humans and chromosome 7 in the mouse. This domain is thought to be under the control of a paternally expressed long noncoding RNA (ncRNA) Kcnq1ot1. The Kcnq1ot1 ncRNA is expressed on the paternal chromosome due to a differentially methylation region located within its promoter. The promoter is methylated on the maternal allele thus inhibiting ncRNA expression, whereas the promoter is unmethylated on the paternal allele. In the placenta, a most of the genes located within a one mega-basepair region are exclusively expressed from the maternal chromosome, whereas the transcripts on the paternal chromosome are silenced by the ncRNA. The placenta seems to follow the classic idea of an imprinted domain. However, in the embryo and more specifically, in the embryonic heart, this is not the case. In the embryonic heart, only a 400kb region is restricted to maternal expression. In addition, one the genes, Kcnq1, starts out expressed exclusively from the maternal allele in early development but switches to biallelic expression during mid-gestation. The purpose of my research is to determine the underlying complexities that are involved in the regulation of transcripts within the Kcnq1 domain. This involves the Kcnq1 gene itself, which has been shown to transition from mono- to biallelic expression during mid-gestation and the Kcnq1ot1 ncRNA per se. I hypothesize that regulation by the Kcnq1ot1 ncRNA is not occurring in a uniform manner in the embryo; rather, the amount of regulation by the ncRNA is dependent on the developmental stage and specific tissue. In addition, this regulation involves complex interactions between enhancers, insulators and other regulatory elements to control the amount of silencing by the Kcnq1ot1 ncRNA. First, through a series of experiments looking at the Kcnq1 promoter, the mechanism of Kcnq1 paternal expression was determined. It was confirmed that Kcnq1 becomes biallelic during mid-gestation in the heart. Bisulfite mutagenesis and methylation sensitive chromatin immunoprecipitation were used to test the hypothesis that the Kcnq1 promoter was methylated in early development and then lost its methylation mark. However, a lack of methylation disproved this mechanism of paternal Kcnq1 activation. Rather, chromosome conformation capture (3C) determined that the Kcnq1 promoter interacts in a…

Advisors/Committee Members: Engel, Nora;, Shore, Scott K., Soprano, Dianne R., Latham, Keith E., Elefant, Felice;.

Subjects/Keywords: Molecular biology; Genetics;

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APA (6th Edition):

Korostowski, L. (2012). Transcript Regulation within the Kcnq1 Domain. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,235191

Chicago Manual of Style (16th Edition):

Korostowski, Lisa. “Transcript Regulation within the Kcnq1 Domain.” 2012. Doctoral Dissertation, Temple University. Accessed September 20, 2020. http://digital.library.temple.edu/u?/p245801coll10,235191.

MLA Handbook (7th Edition):

Korostowski, Lisa. “Transcript Regulation within the Kcnq1 Domain.” 2012. Web. 20 Sep 2020.

Vancouver:

Korostowski L. Transcript Regulation within the Kcnq1 Domain. [Internet] [Doctoral dissertation]. Temple University; 2012. [cited 2020 Sep 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,235191.

Council of Science Editors:

Korostowski L. Transcript Regulation within the Kcnq1 Domain. [Doctoral Dissertation]. Temple University; 2012. Available from: http://digital.library.temple.edu/u?/p245801coll10,235191

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