scholarly journals Tet1 regulates epigenetic remodeling of the pericentromeric heterochromatin and chromocenter organization in DNA hypomethylated cells

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009646
Author(s):  
Yota Hagihara ◽  
Satoshi Asada ◽  
Takahiro Maeda ◽  
Toru Nakano ◽  
Shinpei Yamaguchi
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Pericentromeric Heterochromatin ◽  
Dna Hypomethylation ◽  
Cellular Events ◽  
Epigenetic Remodeling ◽  
Core Components ◽  
Liquid Liquid Phase Separation ◽  
Prophase Of Meiosis

Pericentromeric heterochromatin (PCH), the constitutive heterochromatin of pericentromeric regions, plays crucial roles in various cellular events, such as cell division and DNA replication. PCH forms chromocenters in the interphase nucleus, and chromocenters cluster at the prophase of meiosis. Chromocenter clustering has been reported to be critical for the appropriate progression of meiosis. However, the molecular mechanisms underlying chromocenter clustering remain elusive. In this study, we found that global DNA hypomethylation, 5hmC enrichment in PCH, and chromocenter clustering of Dnmt1-KO ESCs were similar to those of the female meiotic germ cells. Tet1 is essential for the deposition of 5hmC and facultative histone marks of H3K27me3 and H2AK119ub at PCH, as well as chromocenter clustering. RING1B, one of the core components of PRC1, is recruited to PCH by TET1, and PRC1 plays a critical role in chromocenter clustering. In addition, the rearrangement of the chromocenter under DNA hypomethylated condition was mediated by liquid-liquid phase separation. Thus, we demonstrated a novel role of Tet1 in chromocenter rearrangement in DNA hypomethylated cells.

The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

2020 ◽  
Vol 17 (4) ◽  
pp. 394-401
Author(s):  
Yuanhua Wu ◽  
Yuan Huang ◽  
Jing Cai ◽  
Donglan Zhang ◽  
Shixi Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cell Activity ◽  
Ht22 Cells ◽  
Cerebral Ischemic ◽  
Cerebral Ischemic Reperfusion ◽  
And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

scholarly journals The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons

2021 ◽  
Author(s):  
Hongsheng Wang ◽  
Wanpeng Cui ◽  
Wenbing Chen ◽  
Fang Liu ◽  
Zhaoqi Dong ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Coping With Stress ◽  
Chemical Genetic ◽  
Chronic Social Defeat Stress ◽  
Ventral Tegmental ◽  
Laterodorsal Tegmentum ◽  
Specific Deletion

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

scholarly journals Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism

2011 ◽  
Vol 301 (3) ◽  
pp. H903-H911 ◽  
Author(s):  
Kanchana Karuppiah ◽  
Lawrence J. Druhan ◽  
Chun-an Chen ◽  
Travis Smith ◽  
Jay L. Zweier ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Oxidase Activity ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Caveolin 1 ◽  
Calcium Calmodulin Dependent ◽  
Enos Uncoupling ◽  
Nadph Oxidation ◽  
Interfering Rna

In the vasculature, nitric oxide (NO) is generated by endothelial NO synthase (eNOS) in a calcium/calmodulin-dependent reaction. In the absence of the requisite eNOS cofactor tetrahydrobiopterin (BH4), NADPH oxidation is uncoupled from NO generation, leading to the production of superoxide. Although this phenomenon is apparent with purified enzyme, cellular studies suggest that formation of the BH4 oxidation product, dihydrobiopterin, is the molecular trigger for eNOS uncoupling rather than BH4 depletion alone. In the current study, we investigated the effects of both BH4 depletion and oxidation on eNOS-derived superoxide production in endothelial cells in an attempt to elucidate the molecular mechanisms regulating eNOS oxidase activity. Results demonstrated that pharmacological depletion of endothelial BH4 does not result in eNOS oxidase activity, whereas BH4 oxidation gave rise to significant eNOS-oxidase activity. These findings suggest that the endothelium possesses regulatory mechanisms, which prevent eNOS oxidase activity from pterin-free eNOS. Using a combination of gene silencing and pharmacological approaches, we demonstrate that eNOS-caveolin-1 association is increased under conditions of reduced pterin bioavailability and that this sequestration serves to suppress eNOS uncoupling. Using small interfering RNA approaches, we demonstrate that caveolin-1 gene silencing increases eNOS oxidase activity to 85% of that observed under conditions of BH4 oxidation. Moreover, when caveolin-1 silencing was combined with a pharmacological inhibitor of AKT, BH4 depletion increased eNOS-derived superoxide to 165% of that observed with BH4 oxidation. This study identifies a critical role of caveolin-1 in the regulation of eNOS uncoupling and provides new insight into the mechanisms through which disease-associated changes in caveolin-1 expression may contribute to endothelial dysfunction.

scholarly journals Single-Cell Transcriptomic Analysis Revealed a Critical Role of SPP1/CD44-Mediated Crosstalk Between Macrophages and Cancer Cells in Glioma

2021 ◽  
Vol 9 ◽  
Author(s):  
Cong He ◽  
Luoyan Sheng ◽  
Deshen Pan ◽  
Shuai Jiang ◽  
Li Ding ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Heterogeneity ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Cell Communication ◽  
High Grade Glioma ◽  
Sequencing Analysis ◽  
High Grade ◽  
Cellular Components

High-grade glioma is one of the most lethal human cancers characterized by extensive tumor heterogeneity. In order to identify cellular and molecular mechanisms that drive tumor heterogeneity of this lethal disease, we performed single-cell RNA sequencing analysis of one high-grade glioma. Accordingly, we analyzed the individual cellular components in the ecosystem of this tumor. We found that tumor-associated macrophages are predominant in the immune microenvironment. Furthermore, we identified five distinct subpopulations of tumor cells, including one cycling, two OPC/NPC-like and two MES-like cell subpopulations. Moreover, we revealed the evolutionary transition from the cycling to OPC/NPC-like and MES-like cells by trajectory analysis. Importantly, we found that SPP1/CD44 interaction plays a critical role in macrophage-mediated activation of MES-like cells by exploring the cell-cell communication among all cellular components in the tumor ecosystem. Finally, we showed that high expression levels of both SPP1 and CD44 correlate with an increased infiltration of macrophages and poor prognosis of glioma patients. Taken together, this study provided a single-cell atlas of one high-grade glioma and revealed a critical role of macrophage-mediated SPP1/CD44 signaling in glioma progression, indicating that the SPP1/CD44 axis is a potential target for glioma treatment.

scholarly journals Maternal Hepcidin Suppression Is Essential for Healthy Pregnancy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Veena Sangkhae ◽  
Tomas Ganz ◽  
Elizabeta Nemeth
Keyword(s):  
Iron Deficiency ◽  
Molecular Mechanisms ◽  
Hematological Parameters ◽  
Critical Role ◽  
Physiological Mechanism ◽  
Deficiency Anemia ◽  
Private Company ◽  
Iron Stores ◽  
Primary Mouse

Iron is essential for maternal and fetal health during pregnancy, and iron requirements increase substantially in the second half of gestation1. However, the molecular mechanisms ensuring increased iron availability during pregnancy are not well understood. Hepcidin is the key iron-regulatory hormone and functions by occluding and degrading the iron exporter ferroportin (FPN) to inhibit dietary iron absorption and mobilization of iron from stores. In healthy human and rodent pregnancies, maternal hepcidin decreases starting in the second trimester and is nearly undetectable by late pregnancy2,3 (Figure A). We explored the role of maternal and embryo hepcidin in regulating embryo iron endowment using mouse models. By generating combinations of dams and embryos lacking hepcidin or not, we showed that in normal mouse pregnancy, only maternal but not embryo or placental hepcidin determines embryo iron endowment4. Maternal hepcidin was inversely related to embryo iron stores, and embryos from hepcidin-deficient dams had significantly higher hepatic iron stores regardless of their own hepcidin genotype. When maternal hepcidin was elevated during the second half of pregnancy in mice by administering a hepcidin mimetic, this led to dose-dependent embryo iron deficiency, anemia, and in severe cases, embryo death4. Embryos were particularly sensitive to maternal iron restriction as they developed iron deficiency in the liver and the brain even when maternal hematological parameters were unaffected. These data highlight the critical role of maternal hepcidin suppression for heathy pregnancy. Yet, the physiological mechanism of maternal hepcidin suppression remains unknown. We showed in mice that maternal hepcidin decreases prior to a significant decrease in liver iron and without any changes in serum iron, suggesting that maternal hepcidin suppression is not driven solely by iron deficiency. Using an in vitro model, we determined that the placenta secretes a hepcidin-suppressing factor. Exposure of primary mouse hepatocytes to supernatants from cultured human placenta cells, but not control media, suppressed hepcidin mRNA more than 10-fold (Figure B) and for up to 48hrs. The suppressive factor in the supernatant was >100kDa in size and not associated with exosomes. Studies to identify the placenta-derived hepcidin suppressor are ongoing. In summary, suppression of maternal hepcidin is essential to ensure adequate iron supply for transfer to the fetus and for the increase in maternal red blood cell mass2, and a placenta-derived hepcidin suppressor likely plays an important role in this adaptation. 1Fisher AL and Nemeth E, Am J Clin Nutr, 2017 2Sangkhae V et al, JCI, 2020 3van Santen S et al, Clin Chem Lab Med, 2013 4Sangkhae V et al, Blood, 2020 Figure 1 Disclosures Ganz: Global Blood Therapeutics: Consultancy; Ionis Pharmaceuticals: Consultancy; American Regent: Consultancy; Rockwell: Consultancy; Vifor: Consultancy; Astellas: Consultancy; Akebia: Consultancy; Gossamer Bio: Consultancy; Silarus Therapeutics: Current equity holder in private company; Sierra Oncology: Consultancy; Ambys: Consultancy; Disc Medicine: Consultancy; Intrinsic LifeSciences: Current equity holder in private company. Nemeth:Intrinsic LifeSciences: Current equity holder in private company; Silarus Therapeutics: Current equity holder in private company; Ionis Pharmaceuticals: Consultancy; Protagonist: Consultancy; Vifor: Consultancy.

scholarly journals Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhuo Xie ◽  
Mudan Zhang ◽  
Gaoshi Zhou ◽  
Lihui Lin ◽  
Jing Han ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Critical Role ◽  
Signalling Pathway ◽  
Hedgehog Signalling Pathway ◽  
Inflammatory Bowel ◽  
Effective Drugs

AbstractThe Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.

scholarly journals STAT3 and STAT5 Activation in Solid Cancers

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1428 ◽  
Author(s):  
Sebastian Igelmann ◽  
Heidi Neubauer ◽  
Gerardo Ferbeyre
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Critical Role ◽  
Control Cell ◽  
Cytokine Signaling ◽  
Specific Gene ◽  
Mitochondrial Functions ◽  
Context Dependent

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.

scholarly journals Molecular insights into regulation of JAK2 in myeloproliferative neoplasms

Blood ◽  
2015 ◽  
Vol 125 (22) ◽  
pp. 3388-3392 ◽  
Author(s):  
Olli Silvennoinen ◽  
Stevan R. Hubbard
Keyword(s):  
Molecular Characterization ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Critical Role ◽  
Hematologic Malignancies ◽  
Janus Kinase ◽  
Constitutive Activation

Abstract The critical role of Janus kinase-2 (JAK2) in regulation of myelopoiesis was established 2 decades ago, but identification of mutations in the pseudokinase domain of JAK2 in myeloproliferative neoplasms (MPNs) and in other hematologic malignancies highlighted the role of JAK2 in human disease. These findings have revolutionized the diagnostics of MPNs and led to development of novel JAK2 therapeutics. However, the molecular mechanisms by which mutations in the pseudokinase domain lead to hyperactivation of JAK2 and clinical disease have been unclear. Here, we describe recent advances in the molecular characterization of the JAK2 pseudokinase domain and how pathogenic mutations lead to constitutive activation of JAK2.

ADF/n-cofilin–dependent actin turnover determines platelet formation and sizing

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1767-1775 ◽  
Author(s):  
Markus Bender ◽  
Anita Eckly ◽  
John H. Hartwig ◽  
Margitta Elvers ◽  
Irina Pleines ◽  
...  
Keyword(s):  
Actin Filament ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Actin Dynamics ◽  
Complex Process ◽  
First Time ◽  
Late Stages ◽  
Platelet Formation

Abstract The cellular and molecular mechanisms orchestrating the complex process by which bone marrow megakaryocytes form and release platelets remain poorly understood. Mature megakaryocytes generate long cytoplasmic extensions, proplatelets, which have the capacity to generate platelets. Although microtubules are the main structural component of proplatelets and microtubule sliding is known to drive proplatelet elongation, the role of actin dynamics in the process of platelet formation has remained elusive. Here, we tailored a mouse model lacking all ADF/n-cofilin–mediated actin dynamics in megakaryocytes to specifically elucidate the role of actin filament turnover in platelet formation. We demonstrate, for the first time, that in vivo actin filament turnover plays a critical role in the late stages of platelet formation from megakaryocytes and the proper sizing of platelets in the periphery. Our results provide the genetic proof that platelet production from megakaryocytes strictly requires dynamic changes in the actin cytoskeleton.

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