P>Repetitive elements constitute a substantial proportion of mammalian genomes. These sequences are primarily composed of retrotransposons, which possess cis-regulatory elements that can affect gene regulatory networks if left unchecked. Association between retrotransposon dysregulation and human diseases including cancers and neurodegenerative disorders make it crucial to understand these elements. However, their highly repetitive nature stands in the way of their analyses with short read Next Generation Sequencing (NGS) data. To comprehensively resolve the retrotransposons, I developed the repetitive elements alignment pipeline (REAP) that exploited information ignored by conventional strategies. Employing REAP on single-cell epigenomic datasets, I discovered dysregulated retrotransposo...[ Read more ]

Repetitive elements constitute a substantial proportion of mammalian genomes. These sequences are primarily composed of retrotransposons, which possess cis-regulatory elements that can affect gene regulatory networks if left unchecked. Association between retrotransposon dysregulation and human diseases including cancers and neurodegenerative disorders make it crucial to understand these elements. However, their highly repetitive nature stands in the way of their analyses with short read Next Generation Sequencing (NGS) data. To comprehensively resolve the retrotransposons, I developed the repetitive elements alignment pipeline (REAP) that exploited information ignored by conventional strategies. Employing REAP on single-cell epigenomic datasets, I discovered dysregulated retrotransposon subfamilies in a multiple sclerosis (MS) mouse model, including the MER34B-int subfamily, which was not detected by traditional bioinformatic pipelines. These results not only served as a proof of principle for the pipeline but also revealed novel candidates for studying MS pathogenesis. Applying REAP in mining publicly available NGS datasets will be of great value to analyze the involvement of retrotransposons in a plethora of human pathologies.

In addition to resolving repetitive element subfamilies, integrative analysis with various epigenomic assays can also allow for comprehensive analysis of retrotransposons. I utilized mouse embryonic stem cells as a model to study the function of G9a, a crucial epigenetic repressor, in retrotransposon regulation. Genome-wide analyses of DNA methylation, chromatin accessibility, histone modifications enrichment, insulator protein binding, and chromatin conformations uncovered multiple distinct repression mechanisms involving G9a. Most notably, I discovered the relationship between retrotransposon dysregulation and alteration in the transcriptome, epigenome and 3D genome architecture. Taken together, my results shed light on the molecular mechanism of retrotransposon regulation and the consequences if they evade such pathways.