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Identifying Epigenetic Signatures in Monocytes of HIV-Associated Co-Morbidities

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Item Summary

Title:Identifying Epigenetic Signatures in Monocytes of HIV-Associated Co-Morbidities
Authors:Dye, Christian K.
Contributors:Maunakea, Alika K. (advisor)
Molecular Biosciences and Bioengineering (department)
Keywords:Molecular biology
DNA methylation
epigenetics
immune response
insulin resistance
show 2 moremonocyte
neurocognitive disorders
show less
Date Issued:2020
Publisher:University of Hawai'i at Manoa
Abstract:Persistent immune dysregulation is a prominent feature observed in insulin resistance-associated disorders and neurocognitive disorders. These disorders are especially frequent and occur at a significantly younger age among the HIV-infected population relative to the general population. Regulation of innate immune cells has become an attractive target for understanding the pathogenesis of such disorders, referred to in the HIV-infected population as HIV-associated co-morbidities. However, an understanding of the molecular mechanisms that reside at the interface between immune dysregulation and disease risk has yet to be fully elucidated. Here, I sought to examine monocytes, as their potential relationship to insulin resistance and neurocognitive disorders has been previously observed. Insight into the pathogenesis of HIV co-morbidities may be gleaned by better understanding the molecular mechanisms potentially underlying monocyte functionality from individuals clinically diagnosed with these disorders. Hence, this dissertation’s main goal was to identify the epigenetic aberrations in peripheral monocytes from HIV-infected individuals with insulin resistance, a significant feature associated with cardiometabolic diseases, and HIV-associated neurocognitive disorders, which has previously been linked to insulin resistance and contains characteristics reminiscent of cognitive disorders in the general population. Furthermore, given that premature aging is a feature commonly observed among HIV-infected individuals, elucidating the molecular mechanisms potentially regulating monocyte function in the context of HIV co-morbidities may prove invaluable to gaining insight into age-related disorders of the general population. I therefore focused on DNA methylation and next-generation gene expression profiling of monocytes in a cross-sectional comparative analysis between 1) HIV-infected individuals diagnosed as insulin resistant and insulin sensitive; and 2) HIV-infected individuals diagnosed as mild to severe neurocognitive impairment and no impairment. In Chapter II, I discuss an enrichment strategy of monocytes from peripheral blood leukocytes and isolation of high-quality DNA which was used for DNA methylation analyses. In this study, I observed significant differential DNA methylation at single-nucleotide resolution across the genome between insulin resistant and insulin sensitive HIV-infected adults on stable antiretroviral therapies (ART). I observed that these differentially methylated loci preferentially occurred at genes implicated in insulin and immune response-related functions. Several of these differentially methylated loci were significant predictors of insulin sensitivity status, hinting at a possible molecular biomarker that may distinguishing insulin sensitivity status. Furthermore, I revealed the potential origin of these aberrantly methylated loci of insulin resistance in monocytes, implicating potential defects in epigenetic regulation during hematopoietic stem cell differentiation as being involved in insulin resistant states in monocytes. Using a similar strategy, Chapter III reveals significant differential DNA methylation between cognitively impaired HIV-infected individuals on stable ART as compared to those that were cognitively normal. These significantly differentially methylated loci were enriched at genes associated with neuroactive receptors, immune signaling pathways, and HIV infection. Surprisingly, it was found that neuropsychological test scores were significantly associated with DNA methylation at genes related to cognitive impairment in monocytes and T cells. Furthermore, significant relationships between cognitive impairment-associated DNA methylation patterns and gene expression at genes harboring these differentially methylated loci were observed. Analysis of CD4+ T cells from the same individuals revealed that differences in DNA methylation associated with cognitive impairment are cell type-specific. That is, T cells contain their own DNA methylation profile of cognitive impairment distinct from monocytes. Lastly, given the association of perturbed monocyte function in both insulin resistance and cognitive impairment as well as evidence suggesting a link between insulin resistance and cognitive impairment, I sought to determine if there was any relationship in the DNA methylation profiles between both disorders. Interestingly, I observed little overlap in both datasets—albeit the few overlapping loci were observed at genes involved in monocyte functions and insulin signaling—suggesting DNA methylation patterns in monocytes are disease-specific and monocyte functions in both disorders may be involved in pathogenesis via different cellular functions. To summarize, in this dissertation, I provide initial evidence for aberrant DNA methylation enriched at loci relevant to monocyte cellular activity and pathways functionally relevant to the development of both insulin resistance and neurocognitive dysfunction in the clinical context of these HIV disease patients. These novel findings of differential DNA methylation patterns offers a potential molecular mechanism that may link these HIV co-morbidities to other conditions of premature senescence such as age- and immune-related disorders observed in the general aging population, and provides a foundation for future studies to determine the functional consequences of regulating DNA methylation. Further, this body of work has significant implications with the respect to the development of novel strategies targeted to monocytes as a means to identify, stratify, and abrogate disease risk via modulating immune networks in monocytes.
Pages/Duration:186 pages
URI:http://hdl.handle.net/10125/69025
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Molecular Biosciences and Bioengineering


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