Displaying publications 21 - 40 of 64 in total

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  1. Fulltext Sumoylation controls the timing of Tup1-mediated transcriptional deactivation
    Ng CH, Akhter A, Yurko N, Burgener JM, Rosonina E, Manley JL
    Nat Commun, 2015 Mar 13;6:6610.
    PMID: 25766875 DOI: 10.1038/ncomms7610
    The small ubiquitin-like modifier (SUMO) is implicated in various cellular activities, including transcriptional regulation. We previously showed that the yeast activator Gcn4 becomes sumoylated during activation, facilitating its eventual promoter eviction and transcriptional shut off. Here we show that the corepressor Tup1 is sumoylated, at two specific lysines, under various stress conditions. Mutation of these sites has no effect on Tup1 recruitment or RNAP II promoter occupancy immediately following induction. However, Tup1 levels subsequently decrease, while RNAP II and transcription increase in Tup1 mutant cells. Consistent with this, a Tup1 mutant displaying increased sumoylation led to reduced transcription. We also show that coordinated sumoylation of Gcn4 and Tup1 enhances Gcn4 promoter eviction and that multiple Tup1-interacting proteins become sumoylated after stress. Together, our studies provide evidence that coordinated sumoylation of Gcn4, Tup1 and likely other factors dampens activated transcription by stabilizing Tup1 binding and stimulating Gcn4 and RNAP II removal.
    Matched MeSH terms: Transcription, Genetic*
  2. Fulltext RNA-Seq analysis provides insights for understanding photoautotrophic polyhydroxyalkanoate production in recombinant Synechocystis Sp
    Lau NS, Foong CP, Kurihara Y, Sudesh K, Matsui M
    PLoS One, 2014;9(1):e86368.
    PMID: 24466058 DOI: 10.1371/journal.pone.0086368
    The photosynthetic cyanobacterium, Synechocystis sp. strain 6803, is a potential platform for the production of various chemicals and biofuels. In this study, direct photosynthetic production of a biopolymer, polyhydroxyalkanoate (PHA), in genetically engineered Synechocystis sp. achieved as high as 14 wt%. This is the highest production reported in Synechocystis sp. under photoautotrophic cultivation conditions without the addition of a carbon source. The addition of acetate increased PHA accumulation to 41 wt%, and this value is comparable to the highest production obtained with cyanobacteria. Transcriptome analysis by RNA-seq coupled with real-time PCR was performed to understand the global changes in transcript levels of cells subjected to conditions suitable for photoautotrophic PHA biosynthesis. There was lower expression of most PHA synthesis-related genes in recombinant Synechocystis sp. with higher PHA accumulation suggesting that the concentration of these enzymes is not the limiting factor to achieving high PHA accumulation. In order to cope with the higher PHA production, cells may utilize enhanced photosynthesis to drive the product formation. Results from this study suggest that the total flux of carbon is the possible driving force for the biosynthesis of PHA and the polymerizing enzyme, PHA synthase, is not the only critical factor affecting PHA-synthesis. Knowledge of the regulation or control points of the biopolymer production pathways will facilitate the further use of cyanobacteria for biotechnological applications.
    Matched MeSH terms: Transcription, Genetic
  3. Development of a quantitative real-time RT-PCR for kinetic analysis of immediate-early transcripts of rat cytomegalovirus
    Loh HS, Mohd-Azmi ML
    Acta Virol., 2009;53(4):261-9.
    PMID: 19941390
    One-step real-time RT-PCR assay was developed for quantification of the immediate-early (IE), namely IE1 and IE2 transcripts of Rat cytomegalovirus (RCMV), strain ALL-03 in rat embryonic fibroblast cells (REF). This in-house SYBR Green I based RT-PCR was shown to have higher amplification efficiency and detection limit as compared to a commercially available real-time RT-PCR kit in quantifying these two transcripts. The quantification histogram revealed the divergence of transcription activities of the two IE genes. The IE1 transcript had a concentration peak at 7 hrs post infection (p.i.), whereas IE2 transcript at 20 hrs p.i. Regulation of IE expression is critical for determination, whether the infection is going to be abortive, lytic or latent. Therefore, this in-house developed quantitative RT-PCR assay offers an alternative for diagnosis and monitoring of the acute cytomegalovirus (CMV) infection directed at IE transcript detection.
    Matched MeSH terms: Transcription, Genetic
  4. Fulltext Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia
    Yik MY, Azlan A, Rajasegaran Y, Rosli A, Yusoff NM, Moses EJ
    Genes (Basel), 2021 07 30;12(8).
    PMID: 34440361 DOI: 10.3390/genes12081188
    The proliferative capacity and continuous survival of cells are highly dependent on telomerase expression and the maintenance of telomere length. For this reason, elevated expression of telomerase has been identified in virtually all cancers, including leukemias; however, it should be noted that expression of telomerase is sometimes observed later in malignant development. This time point of activation is highly dependent on the type of leukemia and its causative factors. Many recent studies in this field have contributed to the elucidation of the mechanisms by which the various forms of leukemias increase telomerase activity. These include the dysregulation of telomerase reverse transcriptase (TERT) at various levels which include transcriptional, post-transcriptional, and post-translational stages. The pathways and biological molecules involved in these processes are also being deciphered with the advent of enabling technologies such as next-generation sequencing (NGS), ribonucleic acid sequencing (RNA-Seq), liquid chromatography-mass spectrometry (LCMS/MS), and many others. It has also been established that TERT possess diagnostic value as most adult cells do not express high levels of telomerase. Indeed, studies have shown that prognosis is not favorable in patients who have leukemias expressing high levels of telomerase. Recent research has indicated that targeting of this gene is able to control the survival of malignant cells and therefore offers a potential treatment for TERT-dependent leukemias. Here we review the mechanisms of hTERT regulation and deliberate their association in malignant states of leukemic cells. Further, we also cover the clinical implications of this gene including its use in diagnostic, prognostic, and therapeutic discoveries.
    Matched MeSH terms: Transcription, Genetic
  5. Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2- and PI3K-induced STAT1/3 in HepG2 hepatocyte cells
    Chew GS, Myers S, Shu-Chien AC, Muhammad TS
    Mol Cell Biochem, 2014 Mar;388(1-2):25-37.
    PMID: 24242046 DOI: 10.1007/s11010-013-1896-z
    Interleukin-6 (IL-6) is the major activator of the acute phase response (APR). One important regulator of IL-6-activated APR is peroxisome proliferator-activated receptor alpha (PPARα). Currently, there is a growing interest in determining the role of PPARα in regulating APR; however, studies on the molecular mechanisms and signaling pathways implicated in mediating the effects of IL-6 on the expression of PPARα are limited. We previously revealed that IL-6 inhibits PPARα gene expression through CAAT/enhancer-binding protein transcription factors in hepatocytes. In this study, we determined that STAT1/3 was the direct downstream molecules that mediated the Janus kinase 2 (JAK2) and phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways in IL-6-induced repression of PPARα. Treatment of cells with pharmacological inhibitors of JAK2, PI3K, AKT, and mTOR attenuated the inhibitory effect of IL-6 on PPARα protein in a dose-dependent manner. These inhibitors also decreased the IL-6-induced repression of PPARα mRNA expression and promoter activity. Overexpression of STAT1 and STAT3 in HepG2 cells cotransfected with a reporter vector containing this PPARα promoter region revealed that both the expression plasmids inhibited the IL-6-induced repression of PPARα promoter activity. In the presence of inhibitors of JAK2 and mTOR (AG490 and rapamycin, respectively), IL-6-regulated protein expression and DNA binding of STAT1 and STAT3 were either completely or partially inhibited simultaneously, and the IL-6-induced repression of PPARα protein and mRNA was also inhibited. This study has unraveled novel pathways by which IL-6 inhibits PPARα gene transcription, involving the modulation of JAK2/STAT1-3 and PI3K/AKT/mTOR by inducing the binding of STAT1 and STAT3 to STAT-binding sites on the PPARα promoter. Together, these findings represent a new model of IL-6-induced suppression of PPARα expression by inducing STAT1 and STAT3 phosphorylation and subsequent down-regulation of PPARα mRNA expression.
    Matched MeSH terms: Transcription, Genetic
  6. Transcriptional regulation of retinol binding protein 4 by Interleukin-6 via peroxisome proliferator-activated receptor α and CCAAT/Enhancer binding proteins
    Mohd MA, Ahmad Norudin NA, Muhammad TST
    Mol Cell Endocrinol, 2020 04 05;505:110702.
    PMID: 31927097 DOI: 10.1016/j.mce.2020.110702
    Interleukin-6 (IL-6) is a major mediator of the acute phase response (APR) that regulates the transcription of acute phase proteins (APPs) in the liver. During APR, the plasma levels of negative APPs including retinol binding protein 4 (RBP4) are reduced. Activation of the IL-6 receptor and subsequent signaling pathways leads to the activation of transcription factors, including peroxisome proliferator-activated receptor alpha (PPARα) and CCAAT/enhancer binding protein (C/EBP), which then modulate APP gene expression. The transcriptional regulation of RBP4 by IL-6 is not fully understood. Therefore, this study aimed to elucidate the molecular mechanisms of PPARα and C/EBP isoforms in mediating IL-6 regulation of RBP4 gene expression. IL-6 was shown to reduce the transcriptional activity of RBP4, and functional dissection of the RBP4 promoter further identified the cis-acting regulatory elements that are responsible in mediating the inhibitory effect of IL-6. The binding sites for PPARα and C/EBP present in the RBP4 promoter were predicted at -1079 bp to -1057 bp and -1460 bp to -1439 bp, respectively. The binding of PPARα and C/EBPs to their respective cis-acting elements may lead to antagonistic interactions that modulate the IL-6 regulation of RBP4 promoter activity. Therefore, this study proposed a new mechanism of interaction involving PPARα and different C/EBP isoforms. This interaction is necessary for the regulation of RBP4 gene expression in response to external stimuli, particularly IL-6, during physiological changes.
    Matched MeSH terms: Transcription, Genetic*
  7. Fulltext Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation
    Greenwood MP, Greenwood M, Mecawi AS, Antunes-Rodrigues J, Paton JF, Murphy D
    Mol Brain, 2016 Jan 07;9:1.
    PMID: 26739966 DOI: 10.1186/s13041-015-0182-2
    BACKGROUND: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain.

    RESULTS: We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress.

    CONCLUSIONS: We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain.

    Matched MeSH terms: Transcription, Genetic/drug effects
  8. Fulltext Transcription factor CREB3L1 mediates cAMP and glucocorticoid regulation of arginine vasopressin gene transcription in the rat hypothalamus
    Greenwood M, Greenwood MP, Mecawi AS, Loh SY, Rodrigues JA, Paton JF, et al.
    Mol Brain, 2015 Oct 26;8(1):68.
    PMID: 26503226 DOI: 10.1186/s13041-015-0159-1
    BACKGROUND: Arginine vasopressin (AVP), a neuropeptide hormone that functions in the regulation of water homeostasis by controlling water re-absorption at kidneys, is synthesised in supraoptic nucleus and paraventricular nucleus of the hypothalamus. An increase in plasma osmolality stimulates secretion of AVP to blood circulation and induces AVP synthesis in these nuclei. Although studies on mechanism of AVP transcriptional regulation in hypothalamus proposed that cAMP and glucocorticoids positively and negatively regulate Avp expression, respectively, the molecular mechanisms have remained elusive. Recently, we identified CREB3L1 (cAMP-responsive element binding protein 3 like 1) as a putative transcription factor of Avp transcription in the rat hypothalamus. However the mechanism of how CREB3L1 is regulated in response of hyperosmotic stress in the neurons of hypothalamus has never been reported. This study aims to investigate effect of previously reported regulators (cAMP and glucocorticoid) of Avp transcription on transcription factor CREB3L1 in order to establish a molecular explanation for cAMP and glucocorticoids effect on AVP expression.

    RESULTS: The effect of cAMP and glucocorticoid treatment on Creb3l1 was investigated in both AtT20 cells and hypothalamic organotypic cultures. The expression of Creb3l1 was increased in both mRNA and protein level by treatment with forskolin, which raises intracellular cAMP levels. Activation of cAMP by forskolin also increased Avp promoter activity in AtT20 cells and this effect was blunted by shRNA mediated silencing of Creb3l1. The forskolin induced increase in Creb3l1 expression was diminished by combined treatment with dexamethasone, and, in vivo, intraperitoneal dexamethasone injection blunted the increase in Creb3l1 and Avp expression induced by hyperosmotic stress.

    CONCLUSION: Here we shows that cAMP and glucocorticoid positively and negatively regulate Creb3l1 expression in the rat hypothalamus, respectively, and regulation of cAMP on AVP expression is mediated through CREB3L1. This data provides the connection between CREB3L1, a newly identified transcription factor of AVP expression, with the previously proposed mechanism of Avp transcription which extends our understanding in transcription regulation of Avp in the hypothalamus.

    Matched MeSH terms: Transcription, Genetic/drug effects*
  9. Fulltext Control of Polyamine Biosynthesis by Antizyme Inhibitor 1 Is Important for Transcriptional Regulation of Arginine Vasopressin in the Male Rat Hypothalamus
    Greenwood MP, Greenwood M, Paton JF, Murphy D
    Endocrinology, 2015 Aug;156(8):2905-17.
    PMID: 25961839 DOI: 10.1210/en.2015-1074
    The polyamines spermidine and spermine are small cations present in all living cells. In the brain, these cations are particularly abundant in the neurons of the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus, which synthesize the neuropeptide hormones arginine vasopressin (AVP) and oxytocin. We recently reported increased mRNA expression of antizyme inhibitor 1 (Azin1), an important regulator of polyamine synthesis, in rat SON and PVN as a consequence of 3 days of dehydration. Here we show that AZIN1 protein is highly expressed in both AVP- and oxytocin-positive magnocellular neurons of the SON and PVN together with antizyme 1 (AZ1), ornithine decarboxylase, and polyamines. Azin1 mRNA expression increased in the SON and PVN as a consequence of dehydration, salt loading, and acute hypertonic stress. In organotypic hypothalamic cultures, addition of the irreversible ornithine decarboxylase inhibitor DL-2-(difluoromethyl)-ornithine hydrochloride significantly increased the abundance of heteronuclear AVP but not heteronuclear oxytocin. To identify the function of Azin1 in vivo, lentiviral vectors that either overexpress or knock down Azin1 were stereotaxically delivered into the SON and/or PVN. Azin1 short hairpin RNA delivery resulted in decreased plasma osmolality and had a significant effect on food intake. The expression of AVP mRNA was also significantly increased in the SON by Azin1 short hairpin RNA. In contrast, Azin1 overexpression in the SON decreased AVP mRNA expression. We have therefore identified AZIN1, and hence by inference, polyamines as novel regulators of the expression of the AVP gene.
    Matched MeSH terms: Transcription, Genetic
  10. Fulltext The effects of aging on biosynthetic processes in the rat hypothalamic osmoregulatory neuroendocrine system
    Greenwood MP, Greenwood M, Romanova EV, Mecawi AS, Paterson A, Sarenac O, et al.
    Neurobiol Aging, 2018 05;65:178-191.
    PMID: 29494864 DOI: 10.1016/j.neurobiolaging.2018.01.008
    Elderly people exhibit a diminished capacity to cope with osmotic challenges such as dehydration. We have undertaken a detailed molecular analysis of arginine vasopressin (AVP) biosynthetic processes in the supraoptic nucleus (SON) of the hypothalamus and secretory activity in the posterior pituitary of adult (3 months) and aged (18 months) rats, to provide a comprehensive analysis of age-associated changes to the AVP system. By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, we identified differences in pituitary peptides, including AVP, in adult and aged rats under both basal and dehydrated states. In the SON, increased Avp gene transcription, coincided with reduced Avp promoter methylation in aged rats. Based on transcriptome data, we have previously characterized a number of novel dehydration-induced regulatory factors involved in the response of the SON to osmotic cues. We found that some of these increase in expression with age, while dehydration-induced expression of these genes in the SON was attenuated in aged rats. In summary, we show that aging alters the rat AVP system at the genome, transcriptome, and peptidome levels. These alterations however did not affect circulating levels of AVP in basal or dehydrated states.
    Matched MeSH terms: Transcription, Genetic
  11. P-TEFb goes viral
    Zaborowska J, Isa NF, Murphy S
    Bioessays, 2016 07;38 Suppl 1:S75-85.
    PMID: 27417125 DOI: 10.1002/bies.201670912
    Positive transcription elongation factor b (P-TEFb), which comprises cyclin-dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P-TEFb is required for productive elongation of transcription of protein-coding genes by RNA polymerase II (pol II). In addition, P-TEFb-mediated phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P-TEFb could be effective anti-viral agents.
    Matched MeSH terms: Transcription, Genetic*
  12. Fulltext CDK9 inhibitors define elongation checkpoints at both ends of RNA polymerase II-transcribed genes
    Laitem C, Zaborowska J, Isa NF, Kufs J, Dienstbier M, Murphy S
    Nat Struct Mol Biol, 2015 May;22(5):396-403.
    PMID: 25849141 DOI: 10.1038/nsmb.3000
    Transcription through early-elongation checkpoints requires phosphorylation of negative transcription elongation factors (NTEFs) by the cyclin-dependent kinase (CDK) 9. Using CDK9 inhibitors and global run-on sequencing (GRO-seq), we have mapped CDK9 inhibitor-sensitive checkpoints genome wide in human cells. Our data indicate that early-elongation checkpoints are a general feature of RNA polymerase (pol) II-transcribed human genes and occur independently of polymerase stalling. Pol II that has negotiated the early-elongation checkpoint can elongate in the presence of inhibitors but, remarkably, terminates transcription prematurely close to the terminal polyadenylation (poly(A)) site. Our analysis has revealed an unexpected poly(A)-associated elongation checkpoint, which has major implications for the regulation of gene expression. Interestingly, the pattern of modification of the C-terminal domain of pol II terminated at this new checkpoint largely mirrors the pattern normally found downstream of the poly(A) site, thus suggesting common mechanisms of termination.
    Matched MeSH terms: Transcription, Genetic/drug effects*
  13. Fulltext S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells
    Vrzalikova K, Ibrahim M, Vockerodt M, Perry T, Margielewska S, Lupino L, et al.
    Leukemia, 2018 01;32(1):214-223.
    PMID: 28878352 DOI: 10.1038/leu.2017.275
    The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.
    Matched MeSH terms: Transcription, Genetic/genetics*
  14. Transcriptional analysis of nitrogen fixation in Paenibacillus durus during growth in nitrogen-enriched medium
    Halim MA, Choo QC, Ghazali AHA, Wajidi MFF, Najimudin N
    Lett Appl Microbiol, 2021 May;72(5):610-618.
    PMID: 33525052 DOI: 10.1111/lam.13455
    Paenibacillus durus strain ATCC 35681T is a Gram-positive diazotroph that displayed capability of fixing nitrogen even in the presence of nitrate or ammonium. However, the nitrogen fixation activity was detected only at day 1 of growth when cultured in liquid nitrogen-enriched medium. The transcripts of all the nifH homologues were present throughout the 9-day study. When grown in nitrogen-depleted medium, nitrogenase activities occurred from day 1 until day 6 and the nifH transcripts were also present during the course of the study albeit at different levels. In both studies, the absence of nitrogen fixation activity regardless of the presence of the nifH transcripts raised the possibility of a post-transcriptional or post-translational regulation of the system. A putative SigA box sequence was found upstream of the transcription start site of nifB1, the first gene in the major nitrogen fixation cluster. The upstream region of nifB2 showed a promoter recognizable by SigE, a sigma factor normally involved in sporulation.
    Matched MeSH terms: Transcription, Genetic/genetics*
  15. Fulltext Combined protein- and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM
    Maiti AK, Kim-Howard X, Motghare P, Pradhan V, Chua KH, Sun C, et al.
    Hum Mol Genet, 2014 Aug 1;23(15):4161-76.
    PMID: 24608226 DOI: 10.1093/hmg/ddu106
    Integrin alpha M (ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system. We previously identified a missense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecular mechanisms of this variant are incompletely understood. A meta-analysis of published and novel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10(-90), odds ratio (OR) = 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels in monocytes from patients with each rs1143679 genotype. We observed that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' < 'AG' < 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10- to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. We found that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid- and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE.
    Matched MeSH terms: Transcription, Genetic
  16. Fulltext Global transcriptional analysis of Burkholderia pseudomallei high and low biofilm producers reveals insights into biofilm production and virulence
    Chin CY, Hara Y, Ghazali AK, Yap SJ, Kong C, Wong YC, et al.
    BMC Genomics, 2015;16:471.
    PMID: 26092034 DOI: 10.1186/s12864-015-1692-0
    Chronic bacterial infections occur as a result of the infecting pathogen's ability to live within a biofilm, hence escaping the detrimental effects of antibiotics and the immune defense system. Burkholderia pseudomallei, a gram-negative facultative pathogen, is distinctive in its ability to survive within phagocytic and non-phagocytic cells, to persist in vivo for many years and subsequently leading to relapse as well as the development of chronic disease. The capacity to persist has been attributed to the pathogen's ability to form biofilm. However, the underlying biology of B. pseudomallei biofilm development remains unresolved.
    Matched MeSH terms: Transcription, Genetic/genetics*
  17. The mazEF toxin-antitoxin system as a novel antibacterial target in Acinetobacter baumannii
    Ghafourian S, Good L, Sekawi Z, Hamat RA, Soheili S, Sadeghifard N, et al.
    Mem Inst Oswaldo Cruz, 2014 Jul;109(4):502-5.
    PMID: 25004148
    Although analysis of toxin-antitoxin (TA) systems can be instructive, to date, there is no information on the prevalence and identity of TA systems based on a large panel of Acinetobacter baumannii clinical isolates. The aim of the current study was to screen for functional TA systems among clinical isolates of A. baumannii and to identify the systems' locations. For this purpose, we screened 85 A. baumannii isolates collected from different clinical sources for the presence of the mazEF, relBE and higBA TA genes. The results revealed that the genes coding for the mazEF TA system were commonly present in all clinical isolates of A. baumannii. Reverse transcriptase-polymerase chain reaction analysis showed that transcripts were produced in the clinical isolates. Our findings showed that TA genes are prevalent, harboured by chromosomes and transcribed within A. baumannii. Hence, activation of the toxin proteins in the mazEF TA system should be investigated further as an effective antibacterial strategy against this bacterium.
    Matched MeSH terms: Transcription, Genetic
  18. Fulltext Amoebicidal activity of Cassia angustifolia extract and its effect on Acanthamoeba triangularis autophagy-related gene expression at the transcriptional level
    Boonhok R, Sangkanu S, Norouzi R, Siyadatpanah A, Mirzaei F, Mitsuwan W, et al.
    Parasitology, 2021 Aug;148(9):1074-1082.
    PMID: 33966667 DOI: 10.1017/S0031182021000718
    Cassia angustifolia Vahl. plant is used for many therapeutic purposes, for example, in people with constipation, skin diseases, including helminthic and parasitic infections. In our study, we demonstrated an amoebicidal activity of C. angustifolia extract against Acanthamoeba triangularis trophozoite at a micromolar level. Scanning electron microscopy (SEM) images displayed morphological changes in the Acanthamoeba trophozoite, which included the formation of pores in cell membrane and the membrane rupture. In addition to the amoebicidal activity, effects of the extract on surviving trophozoites were observed, which included cyst formation and vacuolization by a microscope and transcriptional expression of Acanthamoeba autophagy in response to the stress by quantitative polymerase chain reaction. Our data showed that the surviving trophozoites were not transformed into cysts and the trophozoite number with enlarged vacuole was not significantly different from that of untreated control. Molecular analysis data demonstrated that the mRNA expression of AcATG genes was slightly changed. Interestingly, AcATG16 decreased significantly at 12 h post treatment, which may indicate a transcriptional regulation by the extract or a balance of intracellular signalling pathways in response to the stress, whereas AcATG3 and AcATG8b remained unchanged. Altogether, these data reveal the anti-Acanthamoeba activity of C. angustifolia extract and the autophagic response in the surviving trophozoites under the plant extract pressure, along with data on the formation of cysts. These represent a promising plant for future drug development. However, further isolation and purification of an active compound and cytotoxicity against human cells are needed, including a study on the autophagic response at the protein level.
    Matched MeSH terms: Transcription, Genetic/drug effects*
  19. Contribution of transposable elements in the plant's genome
    Sahebi M, Hanafi MM, van Wijnen AJ, Rice D, Rafii MY, Azizi P, et al.
    Gene, 2018 Jul 30;665:155-166.
    PMID: 29684486 DOI: 10.1016/j.gene.2018.04.050
    Plants maintain extensive growth flexibility under different environmental conditions, allowing them to continuously and rapidly adapt to alterations in their environment. A large portion of many plant genomes consists of transposable elements (TEs) that create new genetic variations within plant species. Different types of mutations may be created by TEs in plants. Many TEs can avoid the host's defense mechanisms and survive alterations in transposition activity, internal sequence and target site. Thus, plant genomes are expected to utilize a variety of mechanisms to tolerate TEs that are near or within genes. TEs affect the expression of not only nearby genes but also unlinked inserted genes. TEs can create new promoters, leading to novel expression patterns or alternative coding regions to generate alternate transcripts in plant species. TEs can also provide novel cis-acting regulatory elements that act as enhancers or inserts within original enhancers that are required for transcription. Thus, the regulation of plant gene expression is strongly managed by the insertion of TEs into nearby genes. TEs can also lead to chromatin modifications and thereby affect gene expression in plants. TEs are able to generate new genes and modify existing gene structures by duplicating, mobilizing and recombining gene fragments. They can also facilitate cellular functions by sharing their transposase-coding regions. Hence, TE insertions can not only act as simple mutagens but can also alter the elementary functions of the plant genome. Here, we review recent discoveries concerning the contribution of TEs to gene expression in plant genomes and discuss the different mechanisms by which TEs can affect plant gene expression and reduce host defense mechanisms.
    Matched MeSH terms: Transcription, Genetic/physiology*
  20. Male and female NOD mice differentially express peroxisome proliferator-activated receptors and pathogenic cytokines
    Yaacob NS, Goh KS, Norazmi MN
    Exp. Toxicol. Pathol., 2012 Jan;64(1-2):127-31.
    PMID: 20674317 DOI: 10.1016/j.etp.2010.07.005
    The peroxisome proliferator-activated receptors (PPARs) have been implicated in regulating the immune response. We determined the relative changes in the transcriptional expression of PPAR isoforms (α, γ1 and γ2) and cytokines involved in the pathogenesis of type 1 diabetes (T1D) in the immune cells of 5 weeks, 10 weeks and diabetic male non-obese diabetic (NOD) mice compared to those of female NOD mice from our previous studies, "normalized" against their respective non-obese diabetic resistant (NOR) mice controls. Overall PPARα was significantly more elevated in the macrophages of female NOD mice of all age groups whereas PPARγ, particularly the PPARγ2 isoform was more depressed in the macrophages and CD4(+) lymphocytes of female NOD mice compared to their male counterparts. The pro-inflammatory cytokines, IL-1 and TNFα, as well as the Th1 cytokines, IL-2 and IFNγ were more elevated in female NOD mice whereas the Th2 cytokine, IL-4, was more depressed in these mice compared to their male counterparts. These findings suggest that the preponderance of T1D in female NOD mice may be influenced by the more pronounced changes in the expression of PPAR isoforms and pathogenic cytokines compared to those in male NOD mice.
    Matched MeSH terms: Transcription, Genetic*
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