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Modeling gene regulation

Eunsun Jung, Youngmo Seong, Bohyun Jeon, Young-Soo Kwon, Hoseok Song
MicroRNAs (miRNAs) of the miR-17-92 cluster are overexpressed in human cancers, and their enforced expression is tumorigenic in mouse models. A number of genes are reported to be targets of these miRNAs and are implicated in their tumorigenic potential. However, the mode of action by miRNAs suggests that global analysis of their targets is required to understand their cellular roles. In this study, we globally analyzed AGO2-bound mRNAs and found that the miR-17-92 miRNAs coherently repress multiple targets involved in the destabilization of mRNA...
June 20, 2018: Biochimica et Biophysica Acta
Hao Wu, Kaijie Xiao, Zhixin Tian
Core histones and their PTMs play important roles in regulating gene transcription and other DNA-related processes. The study of core histones PTMs, their cross-talk and functional roles is not only of broad biological significance but also of wide pathological and clinical relevance. Having the strength of comprehensive proteoform identification with 100% amino acid sequence coverage and combinatorial PTMs, top-down proteomics has become the state-of-the-art analytical tool for combinatorial PTM characterization of core histones...
June 20, 2018: Journal of Proteomics
Changhwan Ahn, Hong-Seok Kang, Jae-Hwan Lee, Eui-Ju Hong, Eui-Man Jung, Yeong-Min Yoo, Eui-Bae Jeung
In pancreatic β cells, which produce and secrete insulin, Ca2+ signals contribute to insulin production and secretion. Bisphenol A (BPA) and octylphenol (OP) are reported to increase plasma insulin levels and insulin transcription factors, but regulation of plasma glucose levels did not decrease proportionally to the insulin increase. We hypothesized that BPA and OP disrupt calcium homeostasis resulting in insulin resistance through induction of endoplasmic reticulum (ER) stress. BPA and OP treatment leads to survival of pancreatic β cells against streptozotocin, but despite an increased insulin level, serum glucose regulation is not properly regulated...
June 20, 2018: Toxicology Letters
Gesiele Veríssimo, Aalt Bast, Antje R Weseler
Chronic inflammation and oxidative stress are (sub)cellular processes that enhance each other and contribute to the genesis of many systemic pathologies. The endogenous glucocorticoid cortisol plays an important role in the physiological termination of a pro-inflammatory immune response. However, in conditions of pronounced oxidative stress the anti-inflammatory action of cortisol is impaired. Since grape seed-derived monomeric and oligomeric flavan-3-ols (MOF) have been shown to attenuate both, inflammation and oxidative stress in vitro and in humans, we hypothesized that these compounds are able to maintain the anti-inflammatory activity of cortisol in immune cells in a pro-oxidant environment...
June 20, 2018: Chemico-biological Interactions
Jeremy J Gam, Jonathan Babb, Ron Weiss
MicroRNAs (miRNAs) regulate a majority of protein-coding genes, affecting nearly all biological pathways. However, the quantitative dimensions of miRNA-based regulation are not fully understood. In particular, the implications of miRNA target site location, composition rules for multiple target sites, and cooperativity limits for genes regulated by many miRNAs have not been quantitatively characterized. We explore these aspects of miRNA biology at a quantitative single-cell level using a library of 620 miRNA sensors and reporters that are regulated by many miRNA target sites at different positions...
June 22, 2018: Nature Communications
Haote Han, Chih-Chien Chou, Ruyi Li, Jiangyun Liu, Lin Zhang, Wei Zhu, Jin Hu, Bingxian Yang, Jingkui Tian
Chalocomoracin (CMR), one of the major secondary metabolites found in fungus-infected mulberry leaves, is a potent anticancer agent. However, its anticancer mechanism remains elusive. Here, we demonstrated the potent anti-tumor activity and molecular mechanism of CMR both in vitro and in vivo. We showed for the first time that CMR treatment markedly promoted paraptosis along with extensive cytoplasmic vacuolation derived from the endoplasmic reticulum, rather than apoptosis, in PC-3 and MDA-MB-231cell lines...
June 22, 2018: Scientific Reports
Layal Maatouk, Anne-Claire Compagnion, Maria-Angeles Carrillo-de Sauvage, Alexis-Pierre Bemelmans, Sabrina Leclere-Turbant, Vincent Cirotteau, Mira Tohme, Allen Beke, Michaël Trichet, Virginie Bazin, Bobby N Trawick, Richard M Ransohoff, François Tronche, Bénédicte Manoury, Sheela Vyas
Inflammation is a characteristic feature of Parkinson's disease (PD). We examined the role of TLR9 and its regulation by glucocorticoid receptors (GRs) in degeneration of substantia nigra dopamine neurons (DNs). TLR9 agonist, CpG-ODN, induced DN degeneration in mice lacking GR in microglia but not in controls. TLR9 deletion reduced DN loss in neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. GR regulates TLR9 activation during MPTP neurotoxicity as TLR9 antagonist suppressed increased DN loss in microglia/macrophage GR mutant mice...
June 22, 2018: Nature Communications
Raquel Frenedoso da Silva, Deepanshi Dhar, Komal Raina, Dileep Kumar, Rama Kant, Valeria Helena Alves Cagnon, Chapla Agarwal, Rajesh Agarwal
Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer-related deaths in American men. Proliferating cells have higher need for nutrients and oxygen, triggering angiogenesis that plays a critical role in tumor growth, progression and metastasis. Consequently, immense focus has converged onto inhibitors of angiogenesis in cancer treatment, such as Nintedanib, which has shown exceptional antitumor activity via inhibiting cell proliferation and the resulting tumor growth, primarily due to its combined action on tumor cells, endothelial cells and pericytes...
June 22, 2018: Scientific Reports
J Pucilowska, J Vithayathil, M Pagani, C Kelly, J C Karlo, C Robol, I Morella, A Gozzi, R Brambilla, G E Landreth
The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593-kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits...
June 22, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Luni Emdad, Swadesh K Das, Devanand Sarkar, Paul B Fisher
Prostate cancer (PC) is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized PC approaches 100 percent, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated PC cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for PC bone metastasis. MDA-7/IL-24 is a well-studied cytokine established as a therapeutic in a wide-array of cancers upon delivery as a gene therapy...
June 22, 2018: Molecular Cancer Therapeutics
Jayne F Martin Carli, Charles A LeDuc, Yiying Zhang, George Stratigopoulos, Rudolph L Leibel
SNPs in the first intron of FTO convey effects on adiposity by mechanisms that remain unclear, but appear to include modulation of expression of FTO itself, as well as other genes in cis. FTO expression is lower in fibroblasts and iPSC-derived neurons of individuals segregating for FTO obesity risk alleles. We employed in vitro adipogenesis models to investigate molecular mechanisms by which Fto affects adipocyte development and function. Fto expression is upregulated during adipogenesis, and is required for the maintenance of CEBPB and Cebpd / CEBPD expression in murine and human adipocytes in vitro Fto knockdown decreases both the number of 3T3-L1 cells that differentiate into adipocytes as well as the amount of lipid per mature adipocyte...
June 22, 2018: Journal of Lipid Research
Elad Lax, Moshe Szyf
Drug addiction is a devastating health problem that is a very heavy burden on the individual affected and the society in general. Recent research defines addiction as a neurobehavioral disorder. Underpinning biological mechanisms of drug addiction are abnormal neuronal and brain activity following acute and repeated drug exposure. Abnormal gene expression is found in reward and decision-making brain regions of addicts and in animal models and is possibly responsible for changes in brain function. DNA methylation is an epigenetic modification that regulates gene expression...
2018: Progress in Molecular Biology and Translational Science
Prashanth Rajarajan, Yan Jiang, Bibi S Kassim, Schahram Akbarian
Chromosomal conformations, including promoter-enhancer loops, provide a critical regulatory layer for the transcriptional machinery. Therefore, schizophrenia, a common psychiatric disorder associated with broad changes in neuronal gene expression in prefrontal cortex and other brain regions implicated in psychosis, could be associated with alterations in higher-order chromatin. Here, we review early studies on spatial genome organization in the schizophrenia postmortem brain and discuss how integrative approaches using cell culture and animal model systems could gain deeper insight into the potential roles of higher-order chromatin for the neurobiology of and novel treatment avenues for common psychiatric disease...
2018: Progress in Molecular Biology and Translational Science
Xiaobo Pang, Ke Zhang, Jian Huang, Hangyu Wang, Le Gao, Tao Wang, Yingnan Sun, Long Chen, Jinhui Wang
Bai Xuan Xia Ta Re Pian (BXXTR) is a traditional Uighur medicine ancient prescription in China widely used in the treatment of psoriasis, presenting a high curative rate and few side effects. Given that the active constituents and action mechanism still remain unclear, the aim of this study is to explore the potential active constituents and mechanism of antipsoriasis of BXXTR. Psoriasis-like lesions model in BALB/c mice was induced by Imiquimod (IMQ), including five treatment groups: control group, IMQ-treated group, IMQ-ACITRETIN group (Positive control group), IMQ-BXXTR low dose group, IMQ-BXXTR medium dose group and IMQ-BXXTR high dose group...
June 21, 2018: International Journal of Molecular Sciences
Sophie Crux, Jochen Herms, Mario M Dorostkar
Tcf4 is a transcription factor which regulates neurogenesis and neuronal migration in the brain. In humans, loss of function of Tcf4 leads to the rare neurodevelopmental disorder Pitt-Hopkins syndrome, which is characterized by intellectual disability, developmental delay and autistic behavior. We analyzed the consequences of functional loss of Tcf4 on dendritic spines in mature principal neurons. To this end, we crossed mice in which the DNA-binding domain of the Tcf4 gene is flanked by LoxP sites to mice expressing tamoxifen-inducible cre recombinase in a sparse subset of fluorescently labelled neurons (SlickV line)...
2018: PloS One
Stephanie Pohlmann, Stefanie Scheu, Verena Ziegler, Nicole Schupp, Christian Henninger, Gerhard Fritz
BACKGROUND: The Ras-homologous GTPase Rac1 plays a key role in the regulation of gene expression, cytoskeleton-associated processes and cell death as well as carcinogenesis and inflammation. Here, we investigated the impact of Rac1 signaling on liver-mediated immune homeostasis. METHODS: We employed a constitutive Alb-Cre driven rac1 knock-out and a poly I:C inducible Mx1-Cre based knock-out model and analyzed cytokine expression profiles in liver and other organs under basal situation and following LPS-induced endotoxemia by flow cytometry, qRT-PCR and immunocytochemistry...
June 19, 2018: Biochimica et Biophysica Acta
Verena Kohler, Ankita Vaishampayan, Elisabeth Grohmann
Conjugative plasmid transfer is one of the major mechanisms responsible for the spread of antibiotic resistance and virulence genes. The incompatibility (Inc) 18 group of plasmids is a family of plasmids replicating by the theta-mechanism, whose members have been detected frequently in enterococci and streptococci. Inc18 plasmids encode a variety of antibiotic resistances, including resistance to vancomycin, chloramphenicol and the macrolide-lincosamide-streptogramine (MLS) group of antibiotics. These plasmids comprising insertions of Tn1546 were demonstrated to be responsible for the transfer of vancomycin resistance encoded by the vanA gene from vancomycin resistant enterococci (VRE) to methicillin resistant Staphylococcus aureus (MRSA)...
June 19, 2018: Plasmid
Tomomi Shijo, Hitoshi Warita, Naoki Suzuki, Kensuke Ikeda, Shio Mitsuzawa, Tetsuya Akiyama, Hiroya Ono, Ayumi Nishiyama, Rumiko Izumi, Yasuo Kitajima, Masashi Aoki
Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative syndrome characterized by the systemic loss of motor neurons with prominent astrocytosis and microgliosis in the spinal cord and brain. Astrocytes play an essential role in maintaining extracellular microenvironments that surround motor neurons, and are activated by various insults. Growing evidence points to a non-cell autonomous neurotoxicity caused by chronic and sustained astrocytic activation in patients with neurodegenerative diseases, including ALS...
June 19, 2018: Experimental Neurology
Hong-Bin Wang, Tao Li, Dong-Zhou Ma, Hua Zhi
Neuroblastoma is the most common cancer in infants and the third most common cancer in children after leukemia and brain cancer. The purpose of our study was to investigate the effects of estrogen receptor (ER)-α36 gene silencing on tau protein phosphorylation, cell proliferation, and cell apoptosis in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were treated with estrogen or left untreated, to investigate the effects of estrogen stimulation on ERα36 and the ERK/protein B kinase (AKT) signaling pathway...
June 22, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Hanchao Gao, Qing Zhang, Jicheng Chen, David K C Cooper, Hidetaka Hara, Pengfei Chen, Ling Wei, Yanli Zhao, Jia Xu, Zesong Li, Zhiming Cai, Shaodong Luan, Lisha Mou
Whether porcine cytokines are induced after pig-to-primate xenotransplantation and activate human cells remains unknown. First, we investigated the regulation of porcine IL-6, IFN-γ, IL-1β, and TNF-α in xenotransplantation using an in vitro model in which porcine aortic endothelial cells (PAECs) and porcine peripheral blood mononuclear cells (PBMCs) were stimulated with human serum. Downstream cytokines/chemokines were monitored. Pro-inflammatory cytokines (IL-6, IFN-γ, and IL-1β) and chemokines (IL-8, MCP-1, and CXCL2) were upregulated in the both cell types...
June 22, 2018: Xenotransplantation
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