Epigenetics can be defined as the study of the regulation of cell state by factors that lie outside the primary sequence of the cellular genome. In this thesis, I broadly probe the phenomenon of epigenetic regulation, describing three types of phenomena in detail: cytosine methylation, histone marks, and regulation by noncoding RNAs. In the process, we introduce and develop many mathematical tools of broad applicability in genomic analyses.
Cytosine methylation refers to the phenomenon, ubiquitous in mammals, whereby methylation of particular cytosine residues inactive regions throughout the genome. In the past, the presence or absence of methylation was determined from the genomic sequence by gauging local CpG dinucleotide density. Here, I demonstrate a novel approach leveraging the statistical power of many aligned genomes to construct a conservation-based metric. I apply this approach to the primates, and demonstrate a multiplicity of regions in which conservation-based analysis reverses the assessment of a purely density-driven assessment.
Histone marks are the plurality of small chemical modifications to the histone proteins around which eukaryotic DNA is wrapped. There are several such modifications which tend to be present at active genes; others mark inactive genes. Using ChIP-Seq, a novel technology for mapping such modifications across the genome, I describe the first maps of histone marks in a cancer, the pediatric kidney cancer known as Wilms' tumor. I demonstrate that it is possible to use these maps to track the differentiation pathway by which this tumor arises. I also show how these maps can be used to identify markers of kidney stem cells as well as new pharmaceutical targets.
Finally, I explore the question of how noncoding RNAs—functional transcripts that are not translated into protein—play a role in cell regulation. I demonstrate the direct regulation of the noncoding RNA HOTAIR by the gene HOXA13. This is the first known example of direct regulation of a noncoding RNA by the binding of a transcription factor at the noncoding RNA's promoter. Furthermore, I discover a class of 8 noncoding RNAs which function through a pathway very similar to that of HOTAIR: they are directly regulated by HOXA13 and bind to PRC2 to downregulated target loci.
|Advisor:||Lander, Eric S.|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 70/11, Dissertation Abstracts International|
|Subjects:||Molecular biology, Applied Mathematics, Developmental biology|
|Keywords:||Cytosine methylation, Epigenetics, Histone marks, Kidney cancer, Noncoding RNAs, Wilms tumor|
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