Browsing by Subject "transcriptomics"

Now showing 1 - 4 of 4
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    Integrative Computational Genomics Based Approaches to Uncover the Tissue-Specific Regulatory Networks in Development and Disease
    (2020-03) Srivastava, Rajneesh; Janga, Sarath Chandra; Liu, Xiaowen; Marrs, James A.; Kaplan, Mark H.
    Regulatory protein families such as transcription factors (TFs) and RNA Binding Proteins (RBPs) are increasingly being appreciated for their role in regulating the respective targeted genomic/transcriptomic elements resulting in dynamic transcriptional (TRNs) and post-transcriptional regulatory networks (PTRNs) in higher eukaryotes. The mechanistic understanding of these two regulatory network types require a high resolution tissue-specific functional annotation of both the proteins as well as their target sites. This dissertation addresses the need to uncover the tissue-specific regulatory networks in development and disease. This work establishes multiple computational genomics based approaches to further enhance our understanding of regulatory circuits and decipher the associated mechanisms at several layers of biological processes. This study potentially contributes to the research community by providing valuable resources including novel methods, web interfaces and software which transforms our ability to build high-quality regulatory binding maps of RBPs and TFs in a tissue specific manner using multi-omics datasets. The study deciphered the broad spectrum of temporal and evolutionary dynamics of the transcriptome and their regulation at transcriptional and post transcriptional levels. It also advances our ability to functionally annotate hundreds of RBPs and their RNA binding sites across tissues in the human genome which help in decoding the role of RBPs in the context of disease phenotype, networks, and pathways. The approaches developed in this dissertation is scalable and adaptable to further investigate the tissue specific regulators in any biological systems. Overall, this study contributes towards accelerating the progress in molecular diagnostics and drug target identification using regulatory network analysis method in disease and pathophysiology.
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    Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders
    (Oxford University Press, 2024-03-07) Kelley, Christy M.; Maloney, Bryan; Beck, John S.; Ginsberg, Stephen D.; Liang, Winnie; Lahiri, Debomoy K.; Mufson, Elliott J.; Counts, Scott E.; Psychiatry, School of Medicine
    The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer’s disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I–IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I–II and 47 miRNAs were associated with higher Braak Stages III–IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.
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    RNA-Seq Reveals Acute Manganese Exposure Increases Endoplasmic Reticulum Related and Lipocalin mRNAs in Caenorhabditis elegans
    (Wiley, 2016-02) Rudgalvyte, Martina; Peltonen, Juhani; Lakso, Merja; Nass, Richard; Wong, Garry; Department of Pharmacology and Toxicology, IU School of Medicine
    Manganese (Mn) is an essential nutrient; nonetheless, excessive amounts can accumulate in brain tissues causing manganism, a severe neurological condition. Previous studies have suggested oxidative stress, mitochondria dysfunction, and impaired metabolism pathways as routes for Mn toxicity. Here, we used the nematode Caenorhabditis elegans to analyze gene expression changes after acute Mn exposure using RNA-Seq. L1 stage animals were exposed to 50 mM MnCl2 for 30 min and analyzed at L4. We identified 746 up- and 1828 downregulated genes (FDR corrected p < 0.05; two-fold change) that included endoplasmic reticulum related abu and fkb family genes, as well as six of seven lipocalin-related (lpr) family members. These were also verified by qRT-PCR. RNA interference of lpr-5 showed a dramatic increase in whole body vulnerability to Mn exposure. Our studies demonstrate that Mn exposure alters gene transcriptional levels in different cell stress pathways that may ultimately contribute to its toxic effects.
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    The orchestration of gene expression and the editing role of microRNA
    (Elsevier, 2023-06) Fossum, M.; Kaefer, M.; Herbst, K. W.; Harper, L.; Beckers, G. M. A.; Nelson, C. P.; Garriboli, M.; Nieuwhof-Leppink, A.; Bagli, D.; Kalfa, N.; ESPU Research Committee; Urology, School of Medicine
    In this short educational communication the ESPU Research Committee presents the role of non-coding RNA and how these can affect gene expression. In particular we discuss the role of microRNA on post transcriptional changes and how these may cause pathological conditions within Pediatric Urology and how microRNA could be useful in future clinical practice.