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Results for “MESSENGER-RNA”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Targeting ninjurin 2 by miR-764 regulates hydrogen peroxide (H2O2)-induced neuronal cell death

Highlights: • MicroRNA-764 (miR-764) directly regulates ninjurin2 (NINJ2) expression. • Forced overexpression of miR-764 downregulates NINJ2 in human neuronal cells. • miR-764 inhibitor upregulates NINJ2 in human neuronal cells. • NINJ2 downregulation by miR-764 is cytotoxic to human neuronal cells. • NINJ2 overexpression by lentivirus or mir-764 inhibitor protects neuronal cells from H{sub 2}O{sub 2}. Ninjurin 2 (NINJ2) is a novel adhesion molecule expressed in neurons and glial cells. The current study determined if specific microRNA (miRNA) can regulate NINJ2 expression in human neuronal cells. Sequence analysis of NINJ2 mRNA 3′-untranslated region (3′-UTR) revealed that microRNA-764 (miR-764) putatively targets NINJ2. In SH-SY5Y/SK-N-BE neuronal cells and primary human neurons, lentivirus-mediated overexpression of miR-764 conferred significant repression on NINJ2 3′-UTR luciferase activity and downregulation of NINJ2 mRNA/protein. Conversely, transfection of the miR-764 inhibitor increased NINJ2 mRNA and protein expression in the neuronal cells. Function studies show that NINJ2 downregulation by miR-764 induced significant viability reduction and apoptosis in the neuronal cells. Further, CRISPR/Cas9-mediated NINJ2 knockout mimicked and abolished miR-764-induced actions in SH-SY5Y cells. Conversely, lentivirus-mediated NINJ2 overexpression or transfection of miR-764 inhibitor protected neuronal cells from hydrogen peroxide (H{sub 2}O{sub 2})-induced cell death and apoptosis. Collectively, these results show that NINJ2 is a pro-survival factor in human neuronal cells. miR-764 regulates NINJ2 expression and neuron functions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

FTY720 attenuates intestinal injury and suppresses inflammation in experimental necrotizing enterocolitis via modulating CXCL5/CXCR2 axis

Highlights: • FTY720 reduces weight loss and improves survival in experimental NEC. • FTY720 ameliorates intestinal injury in experimental NEC. • FTY720 attenuates inflammatory response in experimental NEC. • FTY720 down-regulates CXCL5/CXCR2 axis in experimental NEC. Necrotizing enterocolitis (NEC) remains one of the leading causes of death in neonatal infants and new therapeutic strategies for NEC are urgently required. The immunomodulatory agent FTY720 has been shown to have protective effects in various inflammatory diseases. In this study, we hypothesized that treatment with FTY720 confers protection against experimental NEC. Experimental NEC was induced in five-day-old C57BL/6 neonatal mice by hyperosmolar formula feeding plus hypoxia and lipopolysaccharide (LPS) challenges. Induction of NEC resulted in substantial weight loss and high mortality compared to the control group, whereas FTY720 treatment significantly attenuated weight loss and improved survival in NEC-challenged neonatal mice. FTY720 treatment strongly ameliorated NEC-induced intestinal injury with reduced apoptosis and up-regulation of intestinal barrier proteins in the ileal tissues. Furthermore, FTY720 treatment abrogated NEC-initiated intestinal and systemic inflammation with markedly diminished inflammatory cytokines and chemokines. Moreover, FTY720 treatment suppressed NEC-activated CXCL5/CXCR2 axis with down-regulated expression of CXCL5 and CXCR2 at both mRNA and protein levels. Thus, we demonstrate that FTY720 protects neonatal mice against NEC-associated lethality by ameliorating intestinal injury and attenuating inflammation, possibly via its down-regulation of NEC-induced activation of intestinal CXCL5/CXCR2 axis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Knockout of Raptor destabilizes ornithine decarboxylase mRNA and decreases binding of HuR to the ODC transcript in cells exposed to ultraviolet-B irradiation

Non-melanoma skin cancer (NMSC) is the most commonly diagnosed cancer in the United States. Ultraviolet-B (UVB) irradiation is the primary carcinogen responsible for stimulating NMSC development. Ornithine Decarboxylase (ODC), the first rate-limiting enzyme in the synthesis of polyamines, is upregulated in response to a variety of proliferation stimuli, including UVB exposure. Our previous studies have demonstrated regulation of ODC synthesis by the mammalian target of rapamycin complex 1 (mTORC1) in cells transformed by oncogenic Ras. The goal of these studies was to better understand the link between mTORC1 and ODC in nontransformed cells treated with UVB. We show that the ablation of mTORC1 activity by conditional knockout of its essential component Raptor led to decreased levels of ODC protein both before and after exposure to 10 mJ/cm{sup 2} UVB. Moreover, ODC mRNA was destabilized in the absence of Raptor, suggesting post-transcriptional regulation. We have previously shown that the ODC transcript is stabilized by the RNA binding protein (RBP) human antigen R (HuR), and the intracellular localization of HuR responds to changes in mTORC1 activity. To expand these studies, we investigated whether HuR functions to regulate ODC mRNA stability after UVB exposure. Our results show an increased localization of HuR to the cytoplasm after UVB exposure in wild-type cells compared to Raptor knockout cells, and this is accompanied by greater association of HuR with the ODC transcript. These data suggest that the localization of HuR in response to UVB is influenced, at least in part, by mTORC1 and that HuR can bind to and stabilize ODC mRNA after UVB exposure in an mTORC1-dependent manner.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

NRF2 and HSF1 coordinately regulate heme oxygenase-1 expression

Heme oxygenase-1 (HO-1) is an inducible enzyme responding to various stresses and has cytoprotective activities. Although HO-1 has been referred to as heat shock protein (HSP) 32, the heat-mediated induction of HO-1 varies among different species and cell lines. We examined the effects of heat shock on HO-1 expression in mouse embryonic fibroblast (MEF) cells deficient in heat shock factor 1 (HSF1) or nuclear factor-erythroid-2-related factor 2 (NRF2). Heme-induced expression of HO-1 was 2-fold higher in Hsf1{sup −/−} cells than in the wild-type cells at both mRNA and protein levels. In Nrf2{sup −/−} cells, heme-induced expression of HO-1 was not detected. In contrast, HO-1 expression was markedly induced by heat shock at 40–42 °C in Nrf2{sup −/−} cells while the wild-type cells were not responsive. The heat-induced expression of HO-1 in Nrf2{sup −/−} cells were almost completely diminished by transfection of siRNA against Hsf1 gene. These results suggest that HSF1 and NRF2 suppress heme-induced and heat-induced HO-1 expression, respectively.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Intestinal epithelial cell-specific Raptor is essential for high fat diet-induced weight gain in mice

Mammalian target of rapamycin complex 1 (mTORC1) is a major regulator of cell growth and proliferation through fuel sensing. Systemic inhibition of mTOR as well as manipulation of its downstream products prevent diet-induced obesity. The purpose of this study was to determine the consequences of intestine-targeted mTORC1 inhibition. To attenuate intestinal mTORC1 activity, Villin-Cre{sup ER} mice were crossed with Raptor{sup flox/flox} mice, creating an intestinal-specific Raptor null line (i-Raptor −/−). Mice were fed a high fat diet (HFD) and compositional changes as well as food intake levels were assessed. Over a five-week time course, i-Raptor −/− mice consistently gained less body weight on a HFD compared to wildtype (WT) mice secondary to significantly reduced food intake. Importantly, the i-Raptor −/− mice did not appear to be malnourished, demonstrated by their preservation of lean body mass. i-Raptor −/− mice also maintained a normal metabolic profile without significant changes in triglyceride or fasting glucose levels. Further investigation revealed that GDF-15 mRNA expression was significantly enhanced in i-Raptor −/− enterocytes when refed with HFD after overnight starvation. In summary, our study establishes that loss of intestinal specific-mTORC1 is protective of the development of diet-induced obesity by reducing food intake without altering the metabolic profile.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Role of leukotriene B4 12-hydroxydehydrogenase in α-galactosylceramide-pulsed dendritic cell therapy for non-small cell lung cancer

Highlights: • LTB4DH in CD4{sup +} T cells rescued IFN-γ production with PGE{sub 2}. • LTB4DH in CD8{sup +} T cells rescued tumoricidal activity with PGE{sub 2}. • LTB4DH in CD8{sup +} T cells increased the expression of cytotoxic molecules with PGE{sub 2}. Invariant natural killer T (iNKT) cells exhibit potent antitumor effects upon activation by recognizing a specific glycolipid antigen. We previously performed phase I–II clinical studies to utilize iNKT cells using α-galactosylceramide-pulsed dendritic cells and identified leukotriene B4 12-hydroxydehydrogenase (LTB4DH) as a biomarker highly expressed in T cells derived from non-small cell lung cancer (NSCLC) patients who showed prolonged survival in respond to the iNKT cell immunotherapy. Because LTB4DH expression correlated with prolonged survival of NSCLC patients, we considered LTB4DH to play a role in iNKT cell immunotherapy. We herein demonstrate that the overexpression of LTB4DH in CD4{sup +} or CD8{sup +} T cells increases interferon-γ production and tumoricidal activity in the presence of prostaglandin E{sub 2}. Moreover, the expression of granzyme a, granzyme b, and perforin mRNA was increased in LTB4DH-overexpressing cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Serum microRNA-211 as a biomarker for diabetic retinopathy via modulating Sirtuin 1

Highlights: • Serum miR-211 was significantly up-regulated in patients with diabetic retinopathy. • miR-211 was significantly up-regulated associated with diabetes duration. • miR-211 could directly target SIRT1 and may regulate the expression of SIRT1. • Serum miR-211 as a biomarker for diabetic retinopathy via modulating Sirtuin 1. Diabetic retinopathy (DR) is a progressive microvascular complication associated with diabetes, and remains the leading cause of preventable blindness worldwide. Recent studies have revealed that microRNAs (miRNAs) were involving in the physiological and pathophysiological processes of diabetes and its microvascular and macrovascular complications. The purpose of the current investigation is to identify the candidate miR-211 as a novel biomarker for occurrence and progression of DR in clinical study and experimental research. Firstly, miR-211 was considered as a candidate miRNA identifying by miRNA microarray analysis, Venn diagram analysis, real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and receiver operating characteristic curve in clinical study. Then, the predicted Sirtuin 1 (SIRT1) may be the target gene of miR-211 searching by TargetScan 7.2. Moreover, miR-211 was significantly up-regulated, while SIRT1 mRNA significantly down-regulated measuring by qRT-PCR, meanwhile, SIRT1 protein was significantly down-regulated in coincidence with SIRT1 mRNA detecting by western blot, and even aggravated associated with diabetes duration in diabetic retinal tissues of vivo experiment. Additionally, miR-211 was directly targeted SIRT1 confirming by dual-luciferase reporter assay. Furthermore, with transfection of antagomiR-211, the apoptosis of HUVECs was significantly suppressed employing by flow cytometry analysis, nevertheless the viability of HUVECs was significantly promoted exploiting by Cell Counting Kit-8 assay. Finally, SIRT1 mRNA and SIRT1 protein were significantly up-regulated testing by qRT-PCR and western blot respectively in hyperglycemic HUVECs transfected with antagomiR-211 of vitro experiment. Consequently, the current clinical study and experimental research imply that serum miR-211 as a novel biomarker with high sensitivity and specificity could be associated with occurrence and progression of DR via targeting SIRT1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Zoledronate and high glucose levels influence osteoclast differentiation and bone absorption via the AMPK pathway

Highlights: • High glucose suppresses osteoclast differentiation and bone absorption. • ZOL suppresses osteoclast differentiation and bone absorption in high glucose. • The influences on osteoclast above realize via the AMPK pathway. • The expression of NFATc1, SYK, CTSK and TRAP is regulated by AMPK. Bisphosphonates, the main drugs to treat osteoporosis, have been shown to protect against bone loss in diabetic osteoporosis. However, the effects of the bisphosphonate zoledronate (ZOL) on osteoclast differentiation and function in a high glucose environment as well as the involvement of the adenosine activated protein kinase (AMPK) pathway remain unclear. In the current study, RAW264.7 cells were induced into osteoclasts, divided into low glucose, high glucose, low glucose + ZOL, and high glucose + ZOL groups, which were tested for cell proliferation, cell migration, integrity of the osteoclast sealing zone, osteoclast differentiation, bone absorption, and protein and mRNA expression of genes in the AMPK pathway. We demonstrated that high glucose promoted the expression of AMPK, p-AMPK, while inhibited nuclear factor of activated T cells 1 (NFATc1), spleen tyrosine kinase (SYK), cathepsin K (CTSK), and tartrate-resistant acid phosphatase (TRAP), which influenced osteoclast differentiation and bone absorption. Upon addition of ZOL to high glucose, the expression of AMPK, p-AMPK increased and the expression of NFATc1, SYK, CTSK, TRAP decreased, while osteoclast differentiation and bone absorption were further inhibited. Further more, when added Compound C (AMPK antagonist), we found the expression of AMPK, p-AMPK, decreased, whereas NFATc1, SYK, and TRAP increased. In contrast, AMPK and p-AMPK increased and NFATc1, SYK, CTSK and TRAP decreased upon addition of AICAR, an AMPK agonist. In conclusion, the results suggest AMPK has potential as a new target for the treatment of osteoporosis, the high glucose environment promoted RAW264.7 cell migration, but suppressed osteoclast differentiation and bone absorption, and ZOL suppressed osteoclast migration, differentiation, and bone absorption via the AMPK pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Circular RNA HIPK3 exerts oncogenic properties through suppression of miR-124 in lung cancer

Highlights: • CircHIPK3 is upregulated in human lung cancer cells. • CircHIPK3 siRNA inhibits lung cancer cell survival and proliferation. • CircHIPK3 overexpression promotes lung cancer cell survival and proliferation. • CircHIPK3 regulates expression miR-124 and its targets in lung cancer cells. • CircHIPK3 upregulation correlates with miR-124 downregulation in human lung cancer tissues. The current study tested the expression and potential functions of circular RNA HIPK3 (circHIPK3) in human lung cancer. Our results show that circHIPK3 expression is upregulated in established (A549 line) and primary human lung cancer cells, when compared to its low level in the lung epithelial cells. siRNA-mediated silencing of circHIPK3 potently inhibited survival and proliferation of lung cancer cells, but inducing significant apoptosis activation. Contrarily, forced overexpression of circHIPK3 by a lentiviral construct promoted lung cancer cell survival and proliferation. CircHIPK3 acted as a microRNA-124 (miR-124) sponger and regulated the expression of miR-124 mRNA targets, including SphK1, CDK4 and STAT3, in lung cancer cells. Transfection of miR-124 inhibitor significantly inhibited circHIPK3 siRNA-induced lung cancer cell death and apoptosis. At last, we show that circHIPK3 levels are upregulated in human lung cancer tissues, correlated with miR-124 downregulation. The miR-124 targets (SphK1, STAT3 and CDK4) are upregulated in lung cancer tissues. Together, we propose that circHIPK3 promotes lung cancer cell progression possibly by sponging miR-124. These observations indicate a possible novel therapeutic strategy involving circHIPK3-miR-124 pathway against lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Binding of SRSF4 to a novel enhancer modulates splicing of exon 6 of Fas pre-mRNA

Highlights: • SRSF4 expression promotes exon 6 inclusion of Fas pre-mRNA. • A stronger 5′ splice-site of exon 6 is required for SRSF4-mediated regulation on exon 6 splicing. • SRSF4 functionally targets GGGGUG RNA sequence on exon 6. • SRSF4 directly interacts with GGGGUG sequence on exon 6. Alternative splicing of exon 6 in Fas pre-mRNA generates a membrane bound pro-apoptotic isoform or soluble anti-apoptotic isoform. SRSF4 is a member of Arginine-Serine rich (SR) protein family. Here we demonstrate that increased SRSF4 expression stimulates exon 6 inclusion, and that reduced SRSF4 expression promotes exon 6 exclusion. We also show that weaker but not stronger 5’ splice-site strength of exon 6 abolishes the SRSF4 effects on exon 6 splicing. Furthermore, we identified a novel enhancer on exon 6, on which SRSF4 interacts functionally and physically. Our results illustrate a novel regulatory mechanism of Fas pre-mRNA splicing.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Adenylate cyclase 7 regulated by miR-192 promotes ATRA-induced differentiation of acute promyelocytic leukemia cells

Highlights: • AC7 affects cAMP production in APL cells. • Knockdown of AC7 inhibits ATRA-induced differentiation of APL cells. • MiR-192 directly targets 3′ UTR of AC7 mRNA and inhibits its expression. • MiR-192 knockdown promotes ATRA-induced differentiation of APL cells by up-regulating AC7. • AC7 and miR-192 expression levels are associated with the relapse of APL patients. Adenylate cyclase 7 (AC7) has been reported to participate in various biological processes during cancer progression. However, the roles of AC7 in all-trans retinoic acid (ATRA)-induced differentiation of acute promyelocytic leukemia (APL) cells are still unknown. In this study, firstly, our results showed that AC7 affected intracellular cAMP level and influenced ATRA-induced differentiation of APL cells. Secondly, we revealed that miR-192 could directly target AC7 expression and knockdown of miR-192 promoted ATRA-induced APL cell differentiation by regulating AC7 expression. Furthermore, we found that AC7 expression was lower in patients with relapsed APL than that in patients with newly diagnosed APL, while miR-192 expression was relatively higher in patients with relapsed APL. Taken together, our results show that miR-192-mediated AC7 could play important roles in differentiation of APL cells, AC7 and miR-192 might be new biomarkers and therapeutic targets for patients with relapsed APL.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Retinoic acid co-treatment aggravates severity of dioxin-induced skin lesions in hairless mice via induction of inflammatory response

Highlights: • Treatment with retinoic acid (RA) is ineffective for dioxin-induced skin lesions in mice. • Co-treatment with dioxin and RA results in psoriasis-like phenotype not seen under treatment with either compound alone. • Strong inflammation is the most prominent effect induced by combined treatment with dioxin and RA. Exposure to toxic halogenated polyaromatic hydrocarbons, of which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent, induces diverse skin pathologies in humans, including chloracne, hyperkeratosis, hamartomas, etc. While the toxic effects of TCDD have been extensively studied, effective approaches to their treatment are still lacking. Retinoids are commonly used in therapy of acneiform skin diseases. In vitro, retinoids elicit antagonistic effects on keratinocyte differentiation and proliferation, as compared to TCDD, suggesting their potential in treatment of TCDD-induced skin lesions. Nevertheless, the modulation of TCDD activity in skin by retinoids in vivo was never reported. We have used N-TERT keratinocyte cell line and hairless (hr) mice to determine if retinoic acid (RA) can lessen or reverse TCDD-induced effects in vitro and in vivo. RA co-treatment suppressed TCDD-induced changes in the expression of differentiation-associated genes and N-TERT keratinocyte viability in vitro. However, in hairless mice (in vivo), RA/TCDD co-treatment produced more severe effects, than treatment with either of the two compounds individually. RA/TCDD co-application to mouse skin strongly stimulated keratinocyte proliferation, resulting in dramatic epidermal hyperplasia. It has also led to massive immune cell infiltration into the dermis, and increased mRNA expression of inflammation markers, including IL1β, IL6 and S100A7. Thus, retinoids not only appeared ineffective in treatment of TCDD-induced skin lesions in hairless mice, but also resulted in their exaggeration. These in vivo results question previous cell culture-based claims that RA may reduce TCDD-induced skin effects and caution against the reliance on in vitro data in TCDD toxicology research.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

LncRNA cancer susceptibility candidate 15 accelerates the breast cancer cells progression via miR-153–3p/KLF5 positive feedback loop

Highlights: • CASC15 expression level was aberrantly high-expressed in breast cancer tissue specimens and cells. • Loss-of-functional experiments showed that knockdown of CASC15 suppressed the malignant behaviors of breast cancer cells. • CASC15 functioned as ceRNA of miR-153–3p, besides, miR-153–3p targeted the 3‘-UTR of KLF5 mRNA. • KLF5 binds with the promoter region of CASC15 and activates the transcription. Emerging literature have illustrated the vital regulatory roles of long noncoding RNAs (lncRNAs) on the breast cancer tumorigenesis. Although series of researches have been proceeded on the pathogenesis, there are still much of unsolved mysteries worth investigating. This study uncovered that CASC15 expression level was aberrantly high-expressed in breast cancer tissue specimens and cells. Functionally, the loss-of-functional experiments showed that knockdown of CASC15 suppressed the malignant behaviors of breast cancer cells, such as proliferation, invasion and tumor growth in vitro and vivo. Mechanically, we confirmed that CASC15 functioned as a competing endogenous RNA (ceRNA) of miR-153–3p, besides, miR-153–3p targeted the 3‘-UTR of KLF5 mRNA utilizing the bioinformatics online tools, luciferase reporter assay and RNA immunoprecipitation. Interestingly, we confirmed that the transcription factor KLF5 binds with the promoter region of CASC15 and activates the transcription. In conclusion, we validated the positive feedback loop of KLF5/CASC15/miR-153–3p/KLF5 in the acceleration of breast cancer malignant behaviors and tumorigenesis, suggesting the important biologic roles of CASC15 on the breast cancer tumorigenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

SpWRKY6 acts as a positive regulator during tomato resistance to Phytophthora infestans infection

Highlights: • SpWRKY6 acts as a positive regulator of tomato resistance to P. infestans infection. • Over-expressing SpWRKY6 tomato increased resistance to P. infestans by scavenging reactive oxygen species. • SpWRKY6-mediated tomato resistance to P. infestans through regulating the expression level of PR genes. WRKY transcription factors have been widely known to play key regulatory roles in plant disease resistance. In our previous study, characteristics of SpWRKY6 and its role in response to biotic and abiotic stress was studied. To further investigate the function of SpWRKY6 in tomato resistance to Phytophthora infestans (P. infestans), we studied the effects of loss and gain of function of SpWRKY6. Inhibition of SpWRKY6 mRNA accumulation in tomato leaves, using virus-induced gene silencing (VIGS), greatly reduced SpWRKY6 mRNA levels, and compromised tomato resistance to P. infestans. In contrast, overexpressing- SpWRKY6 tomato plants showed enhanced resistance to P. infestans, accompanied by decreased number of necrotic cells, lesion sizes and disease index. Furthermore, after P. infestans infection, the expression levels of pathogenesis related (PR) genes in transgenic tomato plants overexpressed SpWRKY6 were significantly higher than those in wild type plants, while the number of necrotic cells and the reactive oxygen species (ROS) accumulation were fewer and lower. Taken together, these results indicating that SpWRKY6 acts as a positive regulator of tomato resistance to P. infestans infection through regulating the ROS level and the expression level of PR genes along with alleviating cell membrane injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Nuclear import of transcriptional corepressor BCOR occurs through interaction with karyopherin α expressed in human periodontal ligament

Highlights: • Human periodontal ligament cells express karyopherin α (KPNA) of three subclasses. • BCL6 corepressor (BCOR) is translocated to the nucleus by KPNA2, 4, and 6. • BCOR interacts with KPNA through nuclear localization signal 1. • BCOR mutation causing OFCD syndrome downregulates the SMAD4-SHH-NFIC pathways. Mutations in the gene encoding BCL-6 corepressor (BCOR) are responsible for oculofaciocardiodental (OFCD) syndrome, which is a rare X-linked dominant disorder characterized by radiculomegaly of permanent teeth as the most typical symptom. To function as a transcriptional corepressor, BCOR needs to enter the nucleus; however, the molecular pathway for its nuclear translocation during dental root formation remains unclear. The purpose of this study was to determine the mechanism underlying BCOR transport into the nucleus. Our results showed that human periodontal ligament (PDL) cells expressed karyopherin α (KPNA)2, KPNA4, and KPNA6 belonging to a family of nuclear import proteins, which interacted with BCOR in the immunoprecipitation assay. Site-directed mutagenesis targeting the two nuclear localization signals (NLSs) within BCOR reduced its nuclear translocation; however, co-expression of KPNA2, KPNA4, or KPNA6 with BCOR carrying a previously described mutation which eliminated one of the two NLSs significantly increased nuclear accumulation of the mutant BCOR, indicating participation of KPNA in BCOR nuclear translocation. Comparative expression profiling of PDL cells isolated from normal and OFCD patients revealed significant downregulation of SMAD4, GLI1, and nuclear factor 1-C (NFIC) mRNA expression, suggesting that BCOR mutations cause hyperactive root formation in OFCD syndrome by inhibiting SMAD4-Hedgehog-NFIC signaling implicated in dental root development. Our study contributes to understanding of the mechanisms providing nuclear import of BCOR during root formation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The roles of hypoxia-inducible Factor-1 and iron regulatory protein 1 in iron uptake induced by acute hypoxia

Divalent metal transporter 1 (DMT1) and transferrin receptor (TfR1) are vital proteins for cellular iron uptake. These proteins have hypoxia-responsive elements (HREs) in their 5‘-regulatory region, and they are regulated by hypoxia-inducible factor 1α (HIF-1α) transcriptionally under hypoxic condition. Besides, iron regulatory protein 1 (IRP1) regulates DMT1 and TfR1 by binding to iron-responsive elements (IREs) present in their mRNAs to control cellular iron homeostasis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Comprehensive analysis of long noncoding RNA-associated competing endogenous RNA network in cholangiocarcinoma

Highlights: • LncRNAs as a ceRNA can regulate the expression of target genes, which can influence on tumorigenesis and tumor progression. • We firstly developed novel lncRNAs as well as their action mechanisms in CCA. • We identified a total of 1411 differentially expressed lncRNAs, 3494 mRNAs, and 64 miRNAs. • A ceRNA network consisting of 116 lncRNAs, 14 miRNAs and 59 mRNAs was established. Long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which can largely influence on tumorigenesis and tumor progression. However, the role of lncRNA-mediated ceRNAs in cholangiocarcinoma (CCA) remains unknown. This study aimed to develop novel lncRNAs as well as their action mechanisms in CCA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

DPY30 functions in glucose homeostasis via integrating activated histone epigenetic modifications

Highlights: • DPY30 promoted the expression of key glycolytic genes. • DPY30 recruited H3K4me3 on key glycolytic gene promoters. • DPY30 integrated H3K4me3 and H3K9Ac on key glycolytic gene promoters via inhibiting SIRT6 occupancy. Glucose homeostasis is a key event during many physiological and pathological processes. Histone modifications have emerged as vital factors influencing this process. DPY30, a core subunit of SET1/MLL family histone H3K4 methyltransferase complexes, has been reported to be amplified in cancers. However, the role of DPY30 in glucose homeostasis remains unclear. Here we reported that DPY30 regulated H3K4me3 recruitment to control the expression of Hif1α and its targeted glycolytic genes. Specifically, DPY30 promoted H3K9Ac recruitment via inhibiting SIRT6 occupancy on these gene promoters. Finally, we observed significant upregulation of DPY30 mRNA expression in hepatocellular carcinoma samples from datasets. Taken together, our results reveal a critical role of DPY30 in glucose homeostasis and might offer new therapeutic and diagnostic opportunities for cancers.

60 APPLIED LIFE SCIENCES↗