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    Integrated Multi-omics Characterization of Human Disease Models

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    Name:
    Rodriguez_Tomas.pdf
    Embargo:
    2024-08-09
    Size:
    16.40Mb
    Format:
    PDF
    Description:
    Dissertation
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    Authors
    Rodríguez, Tomás cc
    Faculty Advisor
    Erik J. Sontheimer
    Academic Program
    Other
    UMass Chan Affiliations
    RNA Therapeutics Institute
    Document Type
    Doctoral Dissertation
    Publication Date
    2022-06-07
    Keywords
    disease models
    genomics
    transcriptomics
    
    Metadata
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    Abstract
    Animal and cell-based models of human disease offer simplified biological systems for studying the basis of more complex pathologies under well-controlled conditions. An ever-expanding suite of genomic and transcriptomic tools allows us to thoroughly characterize these models, highlighting disease-driving molecular features and exposing novel therapeutic targets. Here, we integrate diverse DNA- and RNA-sequencing strategies to describe the gene-regulatory chromatin landscape of models for hepatoblastoma and retrovirally-infected CD4+ T-cells. We first developed a conditional hepatoblastoma mouse model using doxycycline-inducible YAP1 overexpression and constitutive β-cateninDelN90. We found that YAP1 withdrawal alone is sufficient to trigger tumor regression and substantially increase survival. We reasoned that a thorough chromatin profile of this tumor model during YAP1 withdrawal could reveal YAP1-driven mechanisms of hepatoblastoma tumorigenesis. Our integrated approach revealed 31 novel YAP1-targeted cis-regulatory element-gene pairs. Subsequent validation confirmed that regulation of Jun-Dimerization Protein 2, among others, is both YAP1-dependent and functionally consequential for the hepatoblastoma phenotype in human cells and in hepatic malignancies. To expand our efforts to apply multi-omics technologies to disease models, we next engineered a fluorophore-containing murine leukemia virus (MLV-GFP) stably integrated into Jurkat CD4+ T-cells to report on defective transcriptional silencing by the retroelement-silencing complex, HUSH. A CRISPR knockout screen identified DHX29 as essential for HUSH-mediated silencing of newly-integrated retroviruses. Profiling genomic and transcriptomic features of MLV-GFP Jurkat cells after HUSH and DHX29 knockout revealed their epistatic roles in silencing, and revealed a suite of loci targeted by HUSH. Finally, we used site-specific proteomics and chromatin profiling to identify HUSH-associated factors at the newly integrated proviral reporter.
    DOI
    10.13028/gnw4-0g50
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51127
    Rights
    © 2022 Rodríguez.
    Distribution License
    All Rights Reserved
    ae974a485f413a2113503eed53cd6c53
    10.13028/gnw4-0g50
    Scopus Count
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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