Dixie Mager

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2019)
Endogenous retroviruses drive transcriptional innovation in human cancer (2019)

Transposable element (TE) exaptation is the process of TE incorporation into functional, and in some cases necessary, genes or regulatory units over evolutionary time. I postulate that an analogous process occurs in oncogenesis, wherein TE-derived promoters generate “noisy” transcription and novel transcripts which can then undergo selection to drive cancer transcriptome evolution. Such “onco-exaptation” is reviewed in the context of several cancers including Hodgkin Lymphoma (HL) where it results in expression of the oncogene CSF1R, yet it is unclear how widespread this phenomenon is.I hypothesize that epigenomic dysregulation in cancer leads to a genome-wide derepression of TE-initiated transcripts, some of which have an oncogenic role. To address this hypothesis, I developed a computational tool called ‘LIONS’ to analyze RNA-sequencing data for TE-initiated transcripts. LIONS detects and quantifies TE-initiated transcripts through transcriptome assembly, applies a novel artificial neural network classifier to identify TE promoter events, and compares biological sets of data.Using this tool, I have determined that the transcriptomes of colorectal carcinoma, diffuse large B-cell lymphoma and HL all have an overall increase in TE-initiated transcripts relative to their respective controls. This increase is specifically driven by an increase in endogenous retroviral long terminal repeat (LTR) initiated transcripts. The distribution of this TE transcriptional activity is widely distributed across the genome, yet patterns of co-activation among element families and the recurrent activation of a small sub-set of TEs is evident.One such recurrent TE-initiated transcript is the LOR1a LTR driven expression of the IRF5 oncogene in HL. IRF5, along with CSF1R and a panel of putative oncogenic TE-initiated transcripts were explored as novel biomarkers in HL. Altogether, I propose that the process of onco-exaptation is a novel and distinct mechanism for oncogene activation and a model system for future studies of exaptation and transcriptome evolution.

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Computational Studies of the Genome Dynamics of Mammalian Transposable Elements and Their Relationships to Genes (2012)

No abstract available.

Regulatory Elements within Repeated Elements: A Case Study of NAIP Transcriptional Evolution (2009)

No abstract available.

Regulation of the ETn/MusD of Active Mouse Long Terminal Repeat Retrotransposons (2008)

No abstract available.

Master's Student Supervision (2010 - 2018)
Characterization of IAPLTR1 subclasses and bidirectional promoter activity : "making sense of it all" (2017)

Endogenous retroviruses (ERVs) are over five-times more prevalent than gene coding sequences in the mouse and human genomes (5). The long terminal repeats (LTRs) of these elements are promoter-enhancers that can have many regulatory effects on the host genome (3). Intracisternal A-Particles (IAPs) are a highly active, murine-specific class of ERV that is known to have strong LTR-driven promoter activity (10). In a recent study, a sequence divergence-based subclass nomenclature was suggested for several classes of IAPLTR – including IAPLTR1 (59). However, it remained unknown whether these high (H1) and low (L1) divergence subclasses provided any more biologically relevant information than the current class system (with no subclasses). Some, but not all, IAPLTRs can initiate sense and antisense transcripts and have thus been considered bidirectional promoters; however, due to growing interest in their form and function, a set of criteria has recently been established for what defines a bidirectional promoter and bidirectional reporter constructs have been developed. The research presented in this thesis provides a detailed analysis of bidirectional and unidirectional reporter constructs and provides evidence that bidirectional reporter constructs should be used when assaying bidirectional promoters. Using a bidirectional reporter construct, IAPLTR1 was determined to meet the criteria for a bidirectional promoter. The core promoters for IAPLTR1 and putative transcription factor binding sites that were unique to each subclass were identified. Point mutagenesis experiments revealed that functional divergence accompanied the sequence divergence of H1 and L1 subclasses. In fact, 95% of the total promoter activity of an L1 LTR was removed by changing three base-pairs to resemble the same region of an H1 LTR. The reciprocal experiment resulted in the H1 LTR losing 100% of antisense promoter activity, but maintaining 100% of sense promoter activity. These experiments, among others, provide evidence that the subclass system provides more biologically relevant information than the single IAPLTR1 class, and therefore should be adopted as part of IAP nomenclature.

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Who's the boss? an investigation into the complex relationship between endogenous retroviruses and nearby genes (2011)

Nearly half of the human and mouse genomes is composed of transposable elements (TEs) which are pieces of DNA capable of or once capable of moving to different locations in the genome. These mobile elements can potentially impact host gene expression in a variety of ways either directly through insertional mutagenesis or indirectly by serving as an alternative promoter/enhancer or through modification of splice signals. In order to protect the integrity of the genome, various mechanisms have evolved to silence TEs. Chromatin modifications, namely DNA methylation and histone modifications, represent two methods of transcriptional silencing of transposable elements. In previous studies it has been shown that methylation of short interspersed nucleotide element (SINE) TEs in the plant and mouse genome can “spread” into flanking sequences. I chose to investigate this “spreading” phenomenon with respect to endogenous retroviruses (ERVs) which are highly active in the mouse genome. Direct evidence has been provided for ERVs in the mouse genome inducing the spread of repressive chromatin. However, the ability of ERV-induced “spreading” to impact nearby gene expression has not yet been characterized. In my thesis, I provide evidence for repressive chromatin spreading as an infrequent occurrence with the exception of the B3galtl gene where DNA methylation and repressive histone marks spread from a solitary ERV long terminal repeat (LTR) into the CpG island promoter of the gene, which correlates with reduced gene transcription. In most cases, however, I show that CpG islands are unmethylated despite the presence of a nearby methylated ERV. Furthermore, I show examples of differential epigenetic marking of insertions with the 3’LTR of the insertion located closest to the nearby gene exhibiting hypomethylation. In one case in particular, I show an interesting trend between expression of the CdGAP gene and hypomethylation of the nearby 3’LTR. These results lead to the conclusion that susceptibility to or protection from “spreading” of repressive chromatin marks is a locus-specific event that may be mediated by various factors such as the ERV-gene distance, the presence of a CpG island gene promoter, the chromatin state of the gene promoter, and the expression of the corresponding gene.

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