Browsing by Subject "MicroRNA"

Now showing 1 - 13 of 13

Open Access
Annotated features of domestic cat-Felis catus genome
(BioMed Central Ltd., 2014) Tamaziani G.; Simonov, S.; Dobrynin, P.; Makunin, A.; Logachev, A.; Komissarov, A.; Shevchenko, A.; Brukhin, V.; Cherkasov, N.; Svitin, A.; Koepfli, Klaus-Peter; Pontius, J.; Driscoll, C. A.; Blackistone, K.; Barr, C.; Goldman, D.; Antunes, A.; Quilez, J.; Lorente-Galdos, B.; Alkan C.; Marques Bonet, T.; Menotti-Raymond, M.; David, V. A.; Narfström, K.; O'Brien, S. J.
Background: Domestic cats enjoy an extensive veterinary medical surveillance which has described nearly 250 genetic diseases analogous to human disorders. Feline infectious agents offer powerful natural models of deadly human diseases, which include feline immunodeficiency virus, feline sarcoma virus and feline leukemia virus. A rich veterinary literature of feline disease pathogenesis and the demonstration of a highly conserved ancestral mammal genome organization make the cat genome annotation a highly informative resource that facilitates multifaceted research endeavors.Findings: Here we report a preliminary annotation of the whole genome sequence of Cinnamon, a domestic cat living in Columbia (MO, USA), bisulfite sequencing of Boris, a male cat from St. Petersburg (Russia), and light 30× sequencing of Sylvester, a European wildcat progenitor of cat domestication. The annotation includes 21,865 protein-coding genes identified by a comparative approach, 217 loci of endogenous retrovirus-like elements, repetitive elements which comprise about 55.7% of the whole genome, 99,494 new SNVs, 8,355 new indels, 743,326 evolutionary constrained elements, and 3,182 microRNA homologues. The methylation sites study shows that 10.5% of cat genome cytosines are methylated. An assisted assembly of a European wildcat, Felis silvestris silvestris, was performed; variants between F. silvestris and F. catus genomes were derived and compared to F. catus.Conclusions: The presented genome annotation extends beyond earlier ones by closing gaps of sequence that were unavoidable with previous low-coverage shotgun genome sequencing. The assembly and its annotation offer an important resource for connecting the rich veterinary and natural history of cats to genome discovery. © 2014 Tamazian et al.; licensee BioMed Central Ltd.
Open Access
Biological properties of extracellular vesicles and their physiological functions
(Taylor & Francis, 2015) Yáñez-Mó, M.; Siljander, P. R. M.; Andreu, Z.; Zavec, A. B.; Borràs, F. E.; Buzas, E. I.; Buzas, K.; Casal, E.; Cappello, F.; Carvalho, J.; Colás, E.; Cordeiro-Da, S. A.; Fais, S.; Falcon-Perez, J. M.; Ghobrial, I. M.; Giebel, B.; Gimona, M.; Graner, M.; Gursel, I.; Gursel, M.; Heegaard, N. H. H.; Hendrix, A.; Kierulf, P.; Kokubun, K.; Kosanovic, M.; Kralj-Iglic, V.; Krämer-Albers, E. M.; Laitinen, S.; Lässer, C.; Lener, T.; Ligeti, E.; Line, A.; Lipps, G.; Llorente, A.; Lötvall, J.; Manček-Keber, M.; Marcilla, A.; Mittelbrunn, M.; Nazarenko, I.; Nolte-'t Hoen, E. N. M.; Nyman, T. A.; O'Driscoll, L.; Olivan, M.; Oliveira, C.; Pállinger, E.; Del Portillo, H. A.; Reventós, J.; Rigau, M.; Rohde, E.; Sammar, M.; Sánchez-Madrid, F.; Santarém, N.; Schallmoser, K.; Ostenfeld, M. S.; Stoorvogel, W.; Stukelj, R.; Grein V. D. S.G.; Helena,ü V. M.; Wauben, M. H. M.; De Wever, O.
In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells.While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
Open Access
hsa-miR-497 as a modulator of the expression in the presence or absence of chrna5 in breast cancer
(2017-06) Özgürsoy, Başak
CHRNA5 is an important ligand-gated receptor with roles in addiction and in cancer. In lung cancer, CHRNA5 dysregulation is well known. There is also expression of CHRNA5 in breast cancer cell lines. microRNAs regulate mRNA expression; and different regulatory microRNAs are involved in different cancer types. microRNAs are thus potential biomarkers to diagnose the diseases (e.g. cancer). However, there is no study testing interactions between microRNAs and CHRNA5 in breast cancer. In the present study, mir-497 was found to be one of the most downregulated microRNAs with testable expression levels upon analysis of expression in the breast cancer cell line MCF7 when exposed to CHRNA5 siRNA. RT-qPCR was performed to test the expression level of mir-497. Validated target genes of mir-497 were found to be significantly related to a list of different KEGG pathways significantly (p value < 0.001) among which there were P53 and PI3K-Akt signalling pathways. Mimic-mir-497 treatment, alone or together with CHRNA5 siRNA, was applied on MCF7 cells to understand the interaction between the miRNA and siRNA under investigation. Selected target genes of mir-497 were tested; the most significantly modulated genes were involved in P53 pathway. The results indicated interactions between mir-497 and CHRNA5 however selected targets were not affected by mimicmir- 497. GSE41079 and GSE41074 public datasets containing mRNA and microRNA expression profiles of liver cancer cells treated with mimic-mir-497. Treatment were used to identify novel targets of mir-497 for future use. Immune system was detected in the second place upon REACTOME analysis of GSE41079 and GSE41074. Using multiple online microRNA-mRNA network tools mir-497 mRNA-miRNA networks were extracted for all or only immune genes. The results from network based analyses helped identify additional targets for later use in our mimic-siRNA system.
Open Access
Identification of differentially expressed microRNAs during lipotoxic endoplasmic reticulum stress in RAW264.7 macrophages
(Turkish Biochemistry Society, 2016-06) Nadir, M.; Tufanlı, Ö.; Erbay, E.; Atalay, A.
Objective: Increased fatty acids in the circulation and their accumulation in non-adipose tissues play a significant role in the development of obesity related metabolic and inflammatory disorders such as insulin resistance, diabetes and atherosclerosis. While fat tissue has the ability to store excess fatty acids, uptake of excess fatty acids to other tissues burdens intracellular metabolic organelles such as mitochondria and endoplasmic reticulum (ER), leading to stress response and lipotoxic cell death. Unfolded protein response (UPR) is a key adaptation of the ER to stress. It is still not completely clear how lipids engage the UPR and how UPR manages both the adaptive and destructive consequences under its control. Increasing evidence point to the importance of miRNA regulation of the UPR as well as UPR’s role in miRNA biogenesis. In order to understand how lipids engage the UPR, we set forth to identify microRNAs regulated by lipotoxic ER stress in macrophages. Methods: We stressed the mouse macrophage cell line (RAW 264.7) with a saturated fatty acid, 500μM palmitate, reflecting the levels found in the circulation of obese patients. We analyzed the microRNAome profiles of this cell line using QRT-PCR based miScript miRNA PCR array which contained all known mouse microRNAs in miRBase release16 and performed pathway analysis for potential targets. Results: 227 microRNAs showed altered expression levels; 43 microRNAs above 2 fold difference and 13 microRNAs 3-24 fold difference. Pathway analysis enriched the target mRNAs of these lipotoxic ER stress associated miRNAs. Conclusion: When exposed to high concentrations of saturated fatty acids that can induce ER stress, macrophages display a dynamic range of changes in their microRNAome profiles. Our findings reflect the consequences of lipotoxic stress on circulating monocytes and tissue-associated macrophages in obesity. Further studies are needed to deliniate which UPR arm is reponsible for the microRNA changes reported here.
Open Access
Inositol‐requiring enzyme‐1 regulates phosphoinositide signaling lipids and macrophage growth
(Wiley-VCH Verlag, 2020-11) Hamid, S. M.; Çıtır, M.; Terzi, E. M.; Çimen, İ.; Yıldırım, Zehra; Doğan, Aslı Ekin; Kocatürk, B.; Onat, Umut Inci; Arditi, M.; Weber, C.; Traynor‐Kaplan, A.; Schultz, C.; Erbay, E.
The ER‐bound kinase/endoribonuclease (RNase), inositol‐requiring enzyme‐1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1’s one known, specific RNA target, X box‐binding protein‐1 (XBP1) or the RNA substrates of IRE1‐dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide‐derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross‐talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1’s RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P3) 5‐phosphatase‐2 (INPPL1) is a direct target of miR‐2137, which controls PI(3,4,5)P3 levels in macrophages. The modulation of cellular PI(3,4,5)P3/PIP2 ratio and anabolic mTOR signaling by the IRE1‐induced miR‐2137 demonstrates how the ER can provide a critical input into cell growth decisions.
Open Access
Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal
(American Association for the Advancement of Science (A A A S), 2013) Gao J.; Aksoy, B. A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S. O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; Cerami, E.; Sander, C.; Schultz, N.
The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics. © 2013 American Association for the Advancement of Science.
Open Access
An investigation of microRNAs mapping to breast cancer related genomic gain and loss regions
(Elsevier, 2009) Selcuklu, S. D.; Yakicier, M. C.; Erson, A. E.
Various regions of amplification or loss are observed in breast tumors as a manifestation of genomic instability. To date, numerous oncogenes or tumor suppressors on some of these regions have been characterized. An increasing body of evidence suggests that such regions also harbor microRNA genes with crucial regulatory roles in cellular processes and disease mechanisms, including cancer. Here, we investigated 35 microRNAs localized to common genomic gain and/or loss regions in breast cancers. To examine amplification or loss of these microRNAs as a result of genomic instability, we performed semiquantitative duplex polymerase chain reaction in 20 breast cancer cell lines, 2 immortalized mammary cell lines, and 2 normal DNA controls. A comprehensive DNA fold number change data for 35 microRNA genes on chromosomal gain/loss regions are presented in breast cancer cells. A 23% (8/35) of the investigated microRNAs showed significant fold number increases (greater than fourfold) compared to GAPDH in one or more of the breast cell lines. Although no homozygous deletions were detected, fold number decreases indicating potential loss regions were observed for 26% (9/35) of the investigated microRNAs. Such fold number changes may point out some of these microRNAs as potential targets of the genomic instability regions as oncogene and tumor suppressor candidates. © 2009 Elsevier Inc. All rights reserved.
Open Access
MicroRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours
(BioMed Central Ltd., 2017) Bulkowska, M.; Rybicka, A.; Senses, K. M.; Ulewicz, K.; Witt, K.; Szymanska, J.; Taciak, B.; Klopfleisch, R.; Hellmén, E.; Dolka, I.; Gure, A. O.; Mucha, J.; Mikow, M.; Gizinski, S.; Krol, M.
Background: MicroRNAs may act as oncogenes or tumour suppressor genes, which make these small molecules potential diagnostic/prognostic factors and targets for anticancer therapies. Several common oncogenic microRNAs have been found for canine mammary cancer and human breast cancer. On account of this, large-scale profiling of microRNA expression in canine mammary cancer seems to be important for both dogs and humans. Methods: Expression profiles of 317 microRNAs in 146 canine mammary tumours of different histological type, malignancy grade and clinical history (presence/absence of metastases) and in 25 control samples were evaluated. The profiling was performed using microarrays. Significance Analysis of Microarrays test was applied in the analysis of microarray data (both unsupervised and supervised data analyses were performed). Validation of the obtained results was performed using real-time qPCR. Subsequently, predicted targets for the microRNAs were searched for in miRBase. Results: Results of the unsupervised analysis indicate that the primary factor separating the samples is the metastasis status. Predicted targets for microRNAs differentially expressed in the metastatic vs. non-metastatic group are mostly engaged in cell cycle regulation, cell differentiation and DNA-damage repair. On the other hand, the supervised analysis reveals clusters of differentially expressed microRNAs unique for the tumour type, malignancy grade and metastasis factor. Conclusions: The most significant difference in microRNA expression was observed between the metastatic and non-metastatic group, which suggests a more important role of microRNAs in the metastasis process than in the malignant transformation. Moreover, the differentially expressed microRNAs constitute potential metastasis markers. However, validation of cfa-miR-144, cfa-miR-32 and cfa-miR-374a levels in blood samples did not follow changes observed in the non-metastatic and metastatic tumours.
Open Access
MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer
(John Wiley and Sons Ltd, 2014) Ward, A.; Shukla, K.; Balwierz, A.; Soons, Z.; König, R.; Sahin, O.; Wiemann, S.
Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer.
Open Access
miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance
(Springer Verlag, 2016-06) Mutlu, M.; Raza, U.; Saatci, Ö.; Eyüpoğlu, E.; Yurdusev, E.; Şahin, Ö.
MicroRNAs (miRNAs) are 20–22-nucleotide small endogenous non-coding RNAs which regulate gene expression at post-transcriptional level. In the last two decades, identification of almost 2600 miRNAs in human and their potential to be modulated opened a new avenue to target almost all hallmarks of cancer. miRNAs have been classified as tumor suppressors or oncogenes depending on the phenotype they induce, the targets they modulate, and the tissue where they function. miR-200c, an illustrious tumor suppressor, is one of the highly studied miRNAs in terms of development, stemness, proliferation, epithelial-mesenchymal transition (EMT), therapy resistance, and metastasis. In this review, we first focus on the regulation of miR-200c expression and its role in regulating EMT in a ZEB1/E-cadherin axis-dependent and ZEB1/E-cadherin axis-independent manner. We then describe the role of miR-200c in therapy resistance in terms of multidrug resistance, chemoresistance, targeted therapy resistance, and radiotherapy resistance in various cancer types. We highlight the importance of miR-200c at the intersection of EMT and chemoresistance. Furthermore, we show how miR-200c coordinates several important signaling cascades such as TGF-β signaling, PI3K/Akt signaling, Notch signaling, VEGF signaling, and NF-κB signaling. Finally, we discuss miR-200c as a potential prognostic/diagnostic biomarker in several diseases, but mainly focusing on cancer and its potential application in future therapeutics.
Open Access
The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer
(Impact Journals LLC, 2016) Raza, U.; Saatci, O.; Uhlmann, S.; Ansari, S. A.; Eyüpoglu, E.; Yurdusev, E.; Mutlu, M.; Ersan, P. G.; Altundağ, M. K.; Zhang, J. D.; Dogan, H. T.; Güler, G.; Şahin, Ö.
Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPRCas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a 'molecular switch' between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53- mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis.
Open Access
RAW264.7 makrofajlarında lipotoksik endoplazmik retikulum stres sürecinde ifadesi değişen mikroRNAların tanımlanması
(Türk Biyokimya Derneği, 2016) Nadir, M.; Tufanlı, Özlem; Erbay, Ebru; Atalay, A.
Amaç: Kan dolaşımındaki serbest yağ asitlerinin artışı ve adipoz olmayan dokulardaki birikimi, insülin direnci, diyabet ve ateroskleroz gibi obezite ile ilişkili metabolik ve emflamatuvar hastalıkların gelişiminde önemli rol oynar. Yağ dokusu, fazla olan yağ asidini depolayabilme kabiliyetine sahipken, diğer dokulara ulaşan fazla miktarda yağ asidi, endoplazmik retikulum (ER) ve mitokondri gibi intraselüler metabolik organelleri zorlayarak stres cevabının oluşmasına ve lipotoksik hücre ölümüne neden olur. Katlanmamış protein yanıtı (KPY) endoplazmik retikulumun strese karşı önemli bir adaptasyonudur. Lipidler ile KPY arasındaki ilişkinin nasıl olduğu ve katlanmamış protein yanıtı ile adaptif ve destrüktif sonuçların nasıl yönetildiği halen tam olarak aydınlatılamamıştır. miRNA biyogenezinde KPY'nın rolünün yanı sıra, katlanmamış protein yanıtını düzenleyen miRNAların önemine işaret eden kanıtlar bulunmaktadır. Bu çalışmada lipidler ile KPY arasındaki ilişkiyi anlamak için, makrofajlardaki lipotoksik ER stresi sürecinde düzenlenen mikroRNA'ların tanımlanması amaçlanmıştır.Metod: Fare makrofaj hücre hattına (RAW 264.7), serbest yağ asidi olan 500 µM palmitat -obez hastaların kan dolaşımındaki seviyede- uygulanarak stres oluşturulmuştur. miRBase sürüm 16'daki bilinen tüm fare mikroRNAlarını içeren QRT-PCR temelli miSCRİPT miRNA PCR array sistemi kullanılarak, hücrelerdeki tüm mikroRNAom profili analiz edilmiş ve potansiyel hedefler için yolak analizleri gerçekleştirilmiştir.Bulgular: Lipotoksik ER stres sonucu, 227 mikroRNA'nın ifade seviyesi 2 kat üzerinde değişmiş ve 43'ü 2 kattan fazla,13'ü ise 3-24 kat değişim göstermiştir. Yolak analizi gerçekleştirilerek lipotoksik ER stresi ile ilişkili mikroRNA'ların mRNA hedefleri belirlenmiş ve gruplanmıştır.Sonuç: Makrofajlar, ER stresini indükleyebilen yüksek konsantrasyondaki doymuş yağ asidine maruz bırakıldığında mikroRNAome profillerinde dinamik bir değişim gözlenmektedir. Bulgularımız, obezitedeki doku ilişkili makrofajlar ve kan dolaşımındaki monositlerdeki lipotoksik stres sonuçlarını yansıtmaktadır. Detaylı çalışmalar gerçekleştirilerek, lipotoksik ER stresi sürecinde ifadesinin değiştiğini rapor ettiğimiz mikroRNA değişimlerinden hangi KPY yolağının sorumlu olduğu belirlenebilir.
Open Access
Unfolded protein response regulated mirnas in lipotoxic endoplasmic reticulum stress in macrophages
(2014-07) Terzi, Erdem Murat
The proper functioning and the development of the cell is essential to the fitness of the multicellular organisms - any significant disturbances in cellular mechanisms can lead to a multitude of diseases or death. Among these conditions, the global rise in metabolic diseases like obesity, diabetes and atherosclerosis draw significant research interest focus. Since the prevalence of metabolic disorders in the developed and underdeveloped world is expected to increase further in next decade; understanding the contributing cellular mechanisms is vital for the development of new and effective diagnostic and therapeutic tools against this devastating disease cluster. Among the homeostatic cellular pathways important for health the Unfolded Protein Response (UPR) is highly conserved from yeast to mammals. Aside from most conserved UPR branch Inositol-requiring protein 1(IRE1), the mammalian UPR is composed of three different pathways regulated by IRE1, eukaryotic translation initiation factor 2-alpha kinase 3 (PERK), and activating transcription factor 6 (ATF6). The UPR signaling is activated in response to the accumulation of unfolded or misfolded proteins in ER that leads to endoplasmic reticulum (ER) stress. The goal of the UPR is to re-establish ER homeostasis via inhibition of further protein translation and promoting protein folding. In the case of severe or unresolved ER stress, UPR instead triggers a programmed cell death. Recent studies indicate that noncoding regulatory RNAs such as microRNAs (miRNAs) play important role in both upstream and downstream of the UPR. In this thesis, the regulation of miRNA expression by the different UPR arms are examined in macrophages under lipidinduced or lipotoxic ER stress conditions. The results of PCR array studies of RNA obtained from mouse macrophages stressed with a saturated fatty acid, palmitate (PA) , revealed multiple differentially regulated miRNAs. Among these miRNAs, significantly regulated ones were further examined for their regulation by the different arms of the UPR. Towards this end several complementary approaches were taken: First, significantly regulated microRNAs from microRNA PCR array results were analyzed. Next, macrophages were treated with palmitate after transfection with IRE1 and PERK silencer RNA (siRNA) to assess the role of UPR arms in lipid regulated miRNA regulation and the expression of relevant miRNAs was examined in treated macrophages. As an alternative method, macrophages were treated simultaneously with palmitate and specific inhibitors for IRE1’s endoribonuclease or PERK’s kinase activity. Then miRNA expressions were further examined in IRE1 knock-out mouse embryonic fibroblast (MEF) cell lines transfected with the wild type (WT) IRE or the endoribonuclease domain inactive (RD) mutant of IRE1 to verify the specific regulation of the miRNA by the IRE1’s endoribonuclease activity. As a result, upregulation of miR-2137 expression by palmitate was determined as IRE1-endoribonuclease dependent. Next, potential target mRNAs were examined by the overexpression or knock-down of miR-2137 in macrophages. One possible target mRNA was found to be inositol polyphosphate phosphatase-like 1 (Innpl1) . Aside from miR-2137, miR-33 also showed significant alteration upon PA treatment in macrophages. Since the role of miR-33 in atherosclerosis, obesity and insulin resistance is well established, its expression was studied further in RAW 264.7 macrophage cell line and bone marrow-derived primary macrophages after IRE1 and PERK knock-down with siRNA. ATP-binding cassette, sub-family A (ABC1), member 1 (ABCA1), a known target of miR-33, was investigated as down-stream target of miR-33 in PA treated macrophages, in an IRE1 dependent manner. The results of this study uncovered new UPR regulated miRNAs under lipid stress in macrophages. Excess lipid is one of the prominent causes in metabolic diseases – obesity, atherosclerosis, insulin resistance – and these UPR regulated miRNAs may explain the underlying mechanism behind this set of diseases. Furthermore, the possible gene targets for these miRNAs could be responsible for progression of such conditions. Further studies are needed to reveal the exact mechanisms that can lead to the development of novel therapeutic approaches.