Genetic regulation of epigenetic processes in mouse: DNA methylation and X chromosome inactivation Public Deposited

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  • March 20, 2019
Creator
  • Calaway, John
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Epigenetics is the study of inheritance not encoded by primary DNA sequence. In mammals, epigenetic processes are required for proper development, gene regulation, chromosome function (e.g., X-chromosome inactivation (XCI)), and genome stability. Misregulation of epigenetic processes is typically a hallmark of disease. Epigenetic marks vary depending on genomic position, cell type, environment, time, sex, and even between individuals within a population. Genetic variation is one source of epigenetic variability that has only recently been appreciated. It is unknown how prevalent and to what extent underlying genetic variation influences epigenetic variability, and furthermore, how this epigenetic variability contributes to phenotypic variation within a population. It has been postulated that epigenetic variation between individuals may help solve the `missing heritability' problem. In an attempt to address these questions and further characterize the influence of genetics on epigenetics, I demonstrate that DNA sequence variation in cis affects two epigenetic processes, DNA methylation and XCI. In the first section, I performed a genome-wide allele-specific methylation survey in the mouse brain to show widespread loci that influence nearby DNA methylation at CpGs. These differentially methylated CpGs tend to reside near transcription start sites and may serve a functional role. We estimate that there are roughly 13,000 of these loci genome-wide. Additionally, I show that these strain-specific cis-acting loci also influence a parent-of-origin differentially methylated region in the 3'UTR of the Actn1 gene, which suggests that genetic variation might also influence highly conserved imprinted regions as well. In the second section, I mapped a cis-acting locus called the X-chromosome controlling element (Xce) that influences XCI choice in mouse. I reduced the Xce candidate interval to a 176 kb region located approximately 500 kb proximal to Xist. I extensively characterized the genetic architecture of the new candidate interval in over 300 inbred and wild-caught mice. I conclude that each mouse taxa examined has a different functional Xce allele and there is no sharing. I identified two new Xce alleles (Xcee and (Xcef) that bring the number to six functional alleles in Mus. I propose that structural variation of segmental duplications within this interval explains the presence of multiple functional Xce alleles. Overall these results provide new insights into the genetic regulation of epigenetic processes in mouse. Furthermore, this work creates a foundation for future work to untangle the molecular mechanisms behind differential DNA methylation and X- chromosome inactivation choice.
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  • In Copyright
Advisor
  • Magnuson, Terry
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
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