MYCN in Neuroblastoma: “Old Wine into New Wineskins”

MYCN Proto-Oncogene, BHLH Transcription Factor (MYCN) has been one of the most studied genes in neuroblastoma. It is known for its oncogenetic mechanisms, as well as its role in the prognosis of the disease and it is considered one of the prominent targets for neuroblastoma therapy. In the present work, we attempted to review the literature, on the relation between MYCN and neuroblastoma from all possible mechanistic sites. We have searched the literature for the role of MYCN in neuroblastoma based on the following topics: the references of MYCN in the literature, the gene’s anatomy, along with its transcripts, the protein’s anatomy, the epigenetic mechanisms regulating MYCN expression and function, as well as MYCN amplification. MYCN plays a significant role in neuroblastoma biology. Its functions and properties range from the forming of G-quadraplexes, to the interaction with miRNAs, as well as the regulation of gene methylation and histone acetylation and deacetylation. Although MYCN is one of the most primary genes studied in neuroblastoma, there is still a lot to be learned. Our knowledge on the exact mechanisms of MYCN amplification, etiology and potential interventions is still limited. The knowledge on the molecular mechanisms of MYCN in neuroblastoma, could have potential prognostic and therapeutic advantages.

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Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

10.1101/2020.07.24.219246 ◽

2020 ◽

Author(s):

Federico Miozzo ◽

Luca Stickely ◽

Damla Tas ◽

Nicolas Loncle ◽

Irina Nikonenko ◽

...

Keyword(s):

Transcription Factor ◽

Dopaminergic Neurons ◽

Molecular Mechanisms ◽

Rna Seq ◽

Dopaminergic Neurodegeneration ◽

Midbrain Dopaminergic Neurons ◽

Genetic Epistasis ◽

Mitochondrial Abnormality ◽

And Function

ABSTRACTThe degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinson’s Disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons results in locomotor impairments and mitochondrial abnormality in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modelling and treating PD.

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Regulatory Role of microRNAs Targeting the Transcription Co-Factor ZNF521 in Normal Tissues and Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms22168461 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8461

Author(s):

Emanuela Chiarella ◽

Annamaria Aloisio ◽

Stefania Scicchitano ◽

Heather Mandy Bond ◽

Maria Mesuraca

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Transitional Cell ◽

Biological Functions ◽

Aberrant Expression ◽

Normal Tissues ◽

Novel Mirna ◽

Mirna Expression Profiling ◽

Mirna Deregulation

Powerful bioinformatics tools have provided a wealth of novel miRNA–transcription factor networks crucial in controlling gene regulation. In this review, we focus on the biological functions of miRNAs targeting ZNF521, explaining the molecular mechanisms by which the dysregulation of this axis contributes to malignancy. ZNF521 is a stem cell-associated co-transcription factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells. The aberrant expression of ZNF521 transcripts, frequently associated with miRNA deregulation, has been detected in several tumors including pancreatic, hepatocellular, gastric, bladder transitional cell carcinomas as well as in breast and ovarian cancers. miRNA expression profiling tools are currently identifying a multitude of miRNAs, involved together with oncogenes and TFs in the regulation of oncogenesis, including ZNF521, which may be candidates for diagnostic and prognostic biomarkers of cancer.

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Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

Cell Death and Disease ◽

10.1038/s41419-020-02990-0 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Olivia J. Marola ◽

Stephanie B. Syc-Mazurek ◽

Gareth R. Howell ◽

Richard T. Libby

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Ganglion Cells ◽

Retinal Vessel ◽

Vessel Diameter ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Ganglion Cell Death

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

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Epigenetic Regulation of Apoptosis and Cell Cycle in Osteosarcoma

Sarcoma ◽

10.1155/2011/679457 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 15

Author(s):

Krithi Rao-Bindal ◽

Eugenie S. Kleinerman

Keyword(s):

Cell Cycle ◽

Cell Cycle Regulation ◽

Molecular Mechanisms ◽

Genetic Mutations ◽

Epigenetic Mechanisms ◽

Epigenetic Alterations ◽

Novel Therapeutic Strategies ◽

Cycle Regulation ◽

Insight Into

The role of genetic mutations in the development of osteosarcoma, such as alterations in p53 and Rb, is well understood. However, the significance of epigenetic mechanisms in the progression of osteosarcoma remains unclear and is increasingly being investigated. Recent evidence suggests that epigenetic alterations such as methylation and histone modifications of genes involved in cell cycle regulation and apoptosis may contribute to the pathogenesis of this tumor. Importantly, understanding the molecular mechanisms of regulation of these pathways may give insight into novel therapeutic strategies for patients with osteosarcoma. This paper serves to summarize the described epigenetic mechanisms in the tumorigenesis of osteosarcoma, specifically those pertaining to apoptosis and cell cycle regulation.

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Mechanosensitive Ion Channel Piezo1 Regulates Myocyte Fusion during Skeletal Myogenesis

10.1101/2020.09.27.315242 ◽

2020 ◽

Author(s):

Huascar Pedro Ortuste Quiroga ◽

Shingo Yokoyama ◽

Massimo Ganassi ◽

Kodai Nakamura ◽

Tomohiro Yamashita ◽

...

Keyword(s):

Ion Channel ◽

Molecular Mechanisms ◽

Myoblast Fusion ◽

Mechanical Stimuli ◽

Muscle Satellite Cell ◽

Myotube Formation ◽

Mechanosensitive Ion Channel ◽

And Function ◽

Sirna Knockdown

AbstractMechanical stimuli such as stretch and resistance training are essential to regulate growth and function of skeletal muscle. However, the molecular mechanisms involved in sensing mechanical stress remain unclear. Here, the purpose of this study was to investigate the role of the mechanosensitive ion channel Piezo1 during myogenic progression. Muscle satellite cell-derived myoblasts and myotubes were modified with stretch, siRNA knockdown and agonist-induced activation of Piezo1. Direct manipulation of Piezo1 modulates terminal myogenic progression. Piezo1 knockdown suppressed myoblast fusion during myotube formation and maturation. This was accompanied by downregulation of the fusogenic protein Myomaker. Piezo1 knockdown also lowered Ca2+ influx in response to stretch. Conversely Piezo1 activation stimulated fusion and increased Ca2+ influx in response to stretch. These evidences indicate that Piezo1 is essential for myotube formation and maturation, which may have implications for msucular dystrophy prevention through its role as a mechanosensitive Ca2+ channel.

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DNA methylation regulates transcriptional homeostasis of algal endosymbiosis in the coral modelAiptasia

10.1101/213066 ◽

2017 ◽

Cited By ~ 3

Author(s):

Yong Li ◽

Yi Jin Liew ◽

Guoxin Cui ◽

Maha J Cziesielski ◽

Noura Zahran ◽

...

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

Model System ◽

Epigenetic Mechanism ◽

Symbiotic Relationship ◽

Epigenetic Mechanisms ◽

Genome Wide ◽

Spurious Transcription ◽

Coral Reef Ecosystems

The symbiotic relationship between cnidarians and dinoflagellates is the cornerstone of coral reef ecosystems. Although research is focusing on the molecular mechanisms underlying this symbiosis, the role of epigenetic mechanisms, which have been implicated in transcriptional regulation and acclimation to environmental change, is unknown. To assess the role of DNA methylation in the cnidarian-dinoflagellate symbiosis, we analyzed genome-wide CpG methylation, histone associations, and transcriptomic states of symbiotic and aposymbiotic anemones in the model systemAiptasia. We find methylated genes are marked by histone H3K36me3 and show significant reduction of spurious transcription and transcriptional noise, revealing a role of DNA methylation in the maintenance of transcriptional homeostasis. Changes in DNA methylation and expression show enrichment for symbiosis-related processes such as immunity, apoptosis, phagocytosis recognition and phagosome formation, and unveil intricate interactions between the underlying pathways. Our results demonstrate that DNA methylation provides an epigenetic mechanism of transcriptional homeostasis during symbiosis.

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Insights in the molecular mechanisms of an azole stress adapted laboratory-generated Aspergillus fumigatus strain

Medical Mycology ◽

10.1093/mmy/myaa118 ◽

2021 ◽

Author(s):

Marion Aruanno ◽

Samantha Gozel ◽

Isabelle Mouyna ◽

Josie E Parker ◽

Daniel Bachmann ◽

...

Keyword(s):

Transcription Factor ◽

Aspergillus Fumigatus ◽

Molecular Mechanisms ◽

Drug Transporters ◽

Major Facilitator Superfamily ◽

Ergosterol Biosynthesis ◽

Azole Resistance ◽

Drug Transporter

Abstract Aspergillus fumigatus is the main cause of invasive aspergillosis, for which azole drugs are the first-line therapy. Emergence of pan-azole resistance among A. fumigatus is concerning and has been mainly attributed to mutations in the target gene (cyp51A). However, azole resistance may also result from other mutations (hmg1, hapE) or other adaptive mechanisms. We performed microevolution experiment exposing an A. fumigatus azole-susceptible strain (Ku80) to sub-minimal inhibitory concentration of voriconazole to analyze emergence of azole resistance. We obtained a strain with pan-azole resistance (Ku80R), which was partially reversible after drug relief, and without mutations in cyp51A, hmg1, and hapE. Transcriptomic analyses revealed overexpression of the transcription factor asg1, several ATP-binding cassette (ABC) and major facilitator superfamily transporters and genes of the ergosterol biosynthesis pathway in Ku80R. Sterol analysis showed a significant decrease of the ergosterol mass under voriconazole exposure in Ku80, but not in Ku80R. However, the proportion of the sterol compounds was similar between both strains. To further assess the role of transporters, we used the ABC transporter inhibitor milbemycine oxime (MLB). MLB inhibited transporter activity in both Ku80 and Ku80R and demonstrated some potentiating effect on azole activity. Criteria for synergism were reached for MLB and posaconazole against Ku80. Finally, deletion of asg1 revealed some role of this transcription factor in controlling drug transporter expression, but had no impact on azole susceptibility. This work provides further insight in mechanisms of azole stress adaptation and suggests that drug transporters inhibition may represent a novel therapeutic target. Lay Summary A pan-azole-resistant strain was generated in vitro, in which drug transporter overexpression was a major trait. Analyses suggested a role of the transporter inhibitor milbemycin oxime in inhibiting drug transporters and potentiating azole activity.

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Goosecoid suppresses cell growth and enhances neuronal differentiation of PC12 cells

Journal of Cell Science ◽

10.1242/jcs.113.15.2705 ◽

2000 ◽

Vol 113 (15) ◽

pp. 2705-2713

Author(s):

K. Sawada ◽

Y. Konishi ◽

M. Tominaga ◽

Y. Watanabe ◽

J. Hirano ◽

...

Keyword(s):

Transcription Factor ◽

Neurite Outgrowth ◽

Neuronal Differentiation ◽

Pc12 Cells ◽

Mammalian Cells ◽

Homeobox Gene ◽

S Phase ◽

Bhlh Transcription Factor ◽

Spemann Organizer

In all vertebrate species, the homeobox gene goosecoid serves as a marker of the Spemann organizer tissue. One function of the organizer is the induction of neural tissue. To investigate the role of goosecoid in neuronal differentiation of mammalian cells, we have introduced goosecoid into PC12 cells. Expression of goosecoid resulted in reduced cell proliferation and enhanced neurite outgrowth in response to NGF. Expression of goosecoid led to a decrease in the percentage of S-phase cells and to upregulation of the expression of the neuron-specific markers MAP-1b and neurofilament-L. Analysis of goosecoid mutants revealed that these effects were independent of either DNA binding or homodimerization of Goosecoid. Coexpression of the N-terminal portion of the ets transcription factor PU.1, a protein that can bind to Goosecoid, repressed neurite outgrowth and rescued the proliferation of PC12 cultures. In contrast, expression of the bHLH transcription factor HES-1 repressed goosecoid-mediated neurite outgrowth without changing the proportion of S-phase cells. These results suggest that goosecoid is involved in neuronal differentiation in two ways, by slowing the cell cycle and stimulating neurite outgrowth, and that these two events are separately regulated.

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The role of Asprosin in patients with dilated cardiomyopathy

BMC Cardiovascular Disorders ◽

10.1186/s12872-020-01680-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ming-Shien Wen ◽

Chao-Yung Wang ◽

Jih-Kai Yeh ◽

Chun-Chi Chen ◽

Ming-Lung Tsai ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Mitochondrial Respiration ◽

Cardiovascular Events ◽

Molecular Mechanisms ◽

Major Adverse Cardiovascular Events ◽

Study Cohort ◽

Protective Mechanisms ◽

Mitochondrial Functions ◽

And Function

Abstract Background Asprosin is a novel fasting glucogenic adipokine discovered in 2016. Asprosin induces rapid glucose releases from the liver. However, its molecular mechanisms and function are still unclear. Adaptation of energy substrates from fatty acid to glucose is recently considered a novel therapeutic target in heart failure treatment. We hypothesized that the asprosin is able to modulate cardiac mitochondrial functions and has important prognostic implications in dilated cardiomyopathy (DCM) patients. Methods We prospectively enrolled 50 patients (86% male, mean age 55 ± 13 years) with DCM and followed their 5-year major adverse cardiovascular events from 2012 to 2017. Comparing with healthy individuals, DCM patients had higher asprosin levels (191.2 versus 79.7 ng/mL, P < 0.01). Results During the 5-year follow-up in the study cohort, 16 (32.0%) patients experienced adverse cardiovascular events. Patients with lower asprosin levels (< 210 ng/mL) were associated with increased risks of adverse clinical outcomes with a hazard ratio of 7.94 (95% CI 1.88–33.50, P = 0.005) when compared patients with higher asprosin levels (≥ 210 ng/mL). Using cardiomyoblasts as a cellular model, we showed that asprosin prevented hypoxia-induced cell death and enhanced mitochondrial respiration and proton leak under hypoxia. Conclusions In patients with DCM, elevated plasma asprosin levels are associated with less adverse cardiovascular events in five years. The underlying protective mechanisms of asprosin may be linked to its functions relating to enhanced mitochondrial respiration under hypoxia.

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Progranulin modulates cartilage-specific gene expression via sirtuin 1–mediated deacetylation of the transcription factors SOX9 and P65

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011164 ◽

2020 ◽

Vol 295 (39) ◽

pp. 13640-13650 ◽

Cited By ~ 1

Author(s):

Dongxu Feng ◽

Xiaomin Kang ◽

Ruiqi Wang ◽

He Chen ◽

Kun Zhang ◽

...

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Sirtuin 1 ◽

Cartilage Tissue ◽

Nuclear Accumulation ◽

Specific Gene ◽

Causative Role ◽

Human Cartilage ◽

Cartilage Homeostasis

Progranulin (PGRN) is an autocrine growth factor that exerts crucial roles within cartilage tissue; however, the molecular mechanisms underlying PGRN-mediated cartilage homeostasis remain elusive. In the present study, we investigated the role of PGRN in regulating chondrocyte homeostasis and its therapeutic potential for managing osteoarthritis (OA). We found that PGRN levels are significantly increased in human cartilage in mild OA and that its expression is decreased in the cartilage in severe OA. In vitro, treatment of primary rat chondrocytes with recombinant PGRN significantly enhanced the levels of collagen type II α 1 chain (COL2A1) and aggrecan, and attenuated TNFα-induced up-regulation of matrix metallopeptidase 13 (MMP13) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) in chondrocytes. These effects were abrogated in SIRT1−/− cells, indicating a causative role of SIRT1 in the effects of PGRN on protein expression in chondrocytes. Mechanistically, PGRN increased SIRT1 expression and activity, which reduced the acetylation levels of SRY-box transcription factor (SOX9) and transcription factor P65 (P65) and thereby promoted nuclear translocation of SOX9 and inhibited TNFα-induced P65 nuclear accumulation to maintain chondrocyte homeostasis. In conclusion, our findings reveal a mechanism of action for PGRN that maintains cartilage homeostasis and supports the notion that PGRN up-regulation may be a promising strategy for managing OA.

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