scholarly journals Temporal control of cortico-thalamic neuron specification by regulation of Neurogenin activity and Polycomb repressive complexes

2018 ◽  
Author(s):  
Koji Oishi ◽  
Debbie L. C. van den Berg ◽  
Franç Guillemot
Keyword(s):  
Cortical Neuron ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Thalamic Neuron ◽  
Differentiation Potential ◽  
Fate Specification ◽  
Polycomb Repressive Complexes ◽  
Fate Determinants ◽  
Epigenetic Processes

SummaryNeural progenitor cells (NPCs) in the embryonic mammalian neocortex generate different neuronal subtypes sequentially. A long-standing hypothesis to account for this temporal fate specification process is that NPCs change their differentiation potential over time. However, the molecular mechanisms underlying these temporal changes in NPC properties are poorly understood. Here we show that Neurogenin1 and Neurogenin2 (Neurog1/2), two proneural transcription factors expressed in NPCs throughout cortical neurogenesis, specify the identity of one of the first cortical neuron subtypes generated, layer 6 cortico-thalamic neurons (CTNs). We found that Neurog1/2 specify the CTN fate through regulation of the cortical fate determinants Fezf2 and Foxp2 and that this Neurog-induced programme becomes inactive after the period of CTN production. Two independent mechanisms contribute to the arrest of CTN neuron generation at the end of layer 6 neurogenesis, including a reduction in the transcriptional activity of Neurog1/2 and the deposition of epigenetic repressive modifications mediated by Polycomb repressive complexes at the Foxp2 gene. Therefore, the duration of production of a cortical neuron subtype is controlled by multiple locking mechanisms involving both transcriptional and epigenetic processes.

The Anti-Atherogenic Properties of Sesamin are Mediated via Improved Macrophage Cholesterol Efflux Through PPARγ1-LXRα and MAPK Signaling

2014 ◽  
Vol 84 (1-2) ◽  
pp. 79-91 ◽  
Author(s):  
Amin F. Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Macrophage Cholesterol Efflux

Background: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARγ1 and LXRα, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood. Aim: This study examines the potential effects of sesamin (0, 25, 50, 75, 100 μM) on PPARγ1 and LXRα expression and transcriptional activity as well as macrophage cholesterol efflux. Methods: PPARγ1 and LXRα expression and transcriptional activity are assessed by luciferase reporter assays. Macrophage cholesterol efflux is evaluated by ApoAI-specific cholesterol efflux assays. Results: The 50 μM, 75 μM, and 100 μM concentrations of sesamin up-regulated the expression of PPARγ1 (p< 0.001, p < 0.001, p < 0.001, respectively) and LXRα (p = 0.002, p < 0.001, p < 0.001, respectively) in a concentration-dependent manner. Moreover, 75 μM and 100 μM concentrations of sesamin led to 5.2-fold (p < 0.001) and 6.0-fold (p<0.001) increases in PPAR transcriptional activity and 3.9-fold (p< 0.001) and 4.2-fold (p < 0.001) increases in LXR transcriptional activity, respectively, in a concentration- and time-dependent manner via MAPK signaling. Consistently, 50 μM, 75 μM, and 100 μM concentrations of sesamin improved macrophage cholesterol efflux by 2.7-fold (p < 0.001), 4.2-fold (p < 0.001), and 4.2-fold (p < 0.001), respectively, via MAPK signaling. Conclusion: Our findings shed light on the molecular mechanism(s) underlying sesamin’s anti-atherogenic effects, which seem to be due, at least in part, to its ability to up-regulate PPARγ1 and LXRα expression and transcriptional activity, improving macrophage cholesterol efflux. We anticipate that sesamin may be used as a therapeutic agent for treating atherosclerosis.

Recent approaches for isolating and culturing mouse bone marrow-derived mesenchymal stromal stem cells

2020 ◽  
Vol 15 ◽  
Author(s):  
Basem M. Abdallah ◽  
Hany M. Khattab
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Cellular Heterogeneity ◽  
High Yield ◽  
Mouse Strains ◽  
Mouse Bone Marrow ◽  
Differentiation Potential ◽  
Stromal Stem Cells

: The isolation and culture of murine bone marrow-derived mesenchymal stromal stem cells (mBMSCs) have attracted great interest in terms of the pre-clinical applications of stem cells in tissue engineering and regenerative medicine. In addition, culturing mBMSCs is important for studying the molecular mechanisms of bone remodelling using relevant transgenic mice. Several factors have created challenges in the isolation and high-yield expansion of homogenous mBMSCs; these factors include low frequencies of bone marrow-derived mesenchymal stromal stem cells (BMSCs) in bone marrow, variation among inbred mouse strains, contamination with haematopoietic progenitor cells (HPCs), the replicative senescence phenotype and cellular heterogeneity. In this review, we provide an overview of nearly all protocols used for isolating and culturing mBMSCs with the aim of clarifying the most important guidelines for culturing highly purified mBMSC populations retaining in vitro and in vivo differentiation potential.

scholarly journals The apple C2H2-type zinc finger transcription factor MdZAT10 positively regulates JA-induced leaf senescence by interacting with MdBT2

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Kuo Yang ◽  
Jian-Ping An ◽  
Chong-Yang Li ◽  
Xue-Na Shen ◽  
Ya-Jing Liu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Transcription Factor ◽  
Liquid Chromatography ◽  
Zinc Finger ◽  
Leaf Senescence ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Liquid Chromatography Mass Spectrometry ◽  
Zinc Finger Transcription Factor ◽  
Insight Into

AbstractJasmonic acid (JA) plays an important role in regulating leaf senescence. However, the molecular mechanisms of leaf senescence in apple (Malus domestica) remain elusive. In this study, we found that MdZAT10, a C2H2-type zinc finger transcription factor (TF) in apple, markedly accelerates leaf senescence and increases the expression of senescence-related genes. To explore how MdZAT10 promotes leaf senescence, we carried out liquid chromatography/mass spectrometry screening. We found that MdABI5 physically interacts with MdZAT10. MdABI5, an important positive regulator of leaf senescence, significantly accelerated leaf senescence in apple. MdZAT10 was found to enhance the transcriptional activity of MdABI5 for MdNYC1 and MdNYE1, thus accelerating leaf senescence. In addition, we found that MdZAT10 expression was induced by methyl jasmonate (MeJA), which accelerated JA-induced leaf senescence. We also found that the JA-responsive protein MdBT2 directly interacts with MdZAT10 and reduces its protein stability through ubiquitination and degradation, thereby delaying MdZAT10-mediated leaf senescence. Taken together, our results provide new insight into the mechanisms by which MdZAT10 positively regulates JA-induced leaf senescence in apple.

scholarly journals Transgenic Epigenetics: Using Transgenic Organisms to Examine Epigenetic Phenomena

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Lori A. McEachern
Keyword(s):  
Molecular Mechanisms ◽  
Model Organism ◽  
Evolutionary Conservation ◽  
Model Organisms ◽  
Valuable Insight ◽  
Epigenetic Control ◽  
Transgenic Organisms ◽  
Epigenetic Analysis ◽  
Insight Into ◽  
Epigenetic Processes

Non-model organisms are generally more difficult and/or time consuming to work with than model organisms. In addition, epigenetic analysis of model organisms is facilitated by well-established protocols, and commercially-available reagents and kits that may not be available for, or previously tested on, non-model organisms. Given the evolutionary conservation and widespread nature of many epigenetic mechanisms, a powerful method to analyze epigenetic phenomena from non-model organisms would be to use transgenic model organisms containing an epigenetic region of interest from the non-model. Interestingly, while transgenic Drosophila and mice have provided significant insight into the molecular mechanisms and evolutionary conservation of the epigenetic processes that target epigenetic control regions in other model organisms, this method has so far been under-exploited for non-model organism epigenetic analysis. This paper details several experiments that have examined the epigenetic processes of genomic imprinting and paramutation, by transferring an epigenetic control region from one model organism to another. These cross-species experiments demonstrate that valuable insight into both the molecular mechanisms and evolutionary conservation of epigenetic processes may be obtained via transgenic experiments, which can then be used to guide further investigations and experiments in the species of interest.

Abstract W MP86: Microrna-146a Modulates Neurogenesis And Oligodendrogenesis After Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Xianshuang Liu ◽  
Chopp Michael ◽  
Xinli Wang ◽  
Li Zhang ◽  
Yisheng Cui ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Target Genes ◽  
Artery Occlusion ◽  
Locked Nucleic Acid ◽  
Myelin Proteins ◽  
Oligodendrocyte Progenitor Cells ◽  
Marker Proteins

Background: Neurogenesis and oligodendrogenesis are associated with functional recovery after stroke. However, the molecules that regulate the generation of new neurons and oligodendrocytes have not been fully investigated. MicroRNAs (miRNAs) post-transcriptionally regulate gene expression. MiR-146a has been reported to regulate the immune response in cells, but the role of miR-146a in neural (NPCs) and oligodendrocyte progenitor cells (OPCs) remains unexplored. Methods and Results: Adult Wistar rats were subjected to right middle cerebral artery occlusion (MCAo). In situ hybridization using locked nucleic acid (LNA)probes against miR-146a showed that stroke considerably increased miR-146a density in the subventricular zone (SVZ, 19 ± 1 vs 6 ± 0.1 area/mm2 in non-MCAo group, p<0.05, n=4/group) and corpus callosum (24 ± 3 vs 8±1 area/mm2 in non-MCAo group) of the ischemic hemisphere. Quantitative RT-PCR also demonstrated a marked upregulation of miR-146a transcript in ischemic NPCs (8.5 fold), suggesting an important role in stroke-induced neurogenesis and oligodendrogenesis. To test its biological function, we over-expressed miR-146a in neural progenitor cells by transfection of miR-146a mimics using nucleofector and found that elevation of miR-146a significantly increased the percentage of Tuj1+ neuroblasts (5 ± 0.3 vs 1 ± 0.2%, p<0.05, n=6/group) and O4+ OPCs (10 ± 1 vs 4 ± 0.4%, p<0.05). Moreover, over-expression of miR-146a in primary cultured OPCs significantly increased several myelin proteins including MBP and PLP, and decreased levels of OPC marker proteins including PDGFRα and NG2, whereas attenuation of miR-146a by siRNA against miR-146a suppressed myelin proteins and augmented OPC marker proteins. Furthermore, miR-146a levels in the OPCs were inversely related to IRAK1 proteins, one of miR-146a target genes. Attenuation of IRAK1 in OPCs substantially increased myelin proteins, indicating that miR-146a mediates oligodendrocyte maturation via targeting IRAK1. Conclusion: Our data provide new insight into molecular mechanisms underlying stroke-induced neurogenesis and oligodendrogenesis by revealing a novel role of miR-146a in NPCs and OPCs, which has potential to be used as a new therapy for neurorecovery after stroke.

Abstract 340: From Stem Cells to Cardiomyocytes: HDAC1 Induces Cardiovascular Differentiation by Regulating SOX17-BMP2 Expression in Early Development.

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Eneda Hoxha ◽  
Erin Lambers ◽  
Veronica Ramirez ◽  
Prasanna Krishnamurthy ◽  
Suresh Verma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Es Cells ◽  
Ips Cells ◽  
Full Potential ◽  
Pluripotent Cells ◽  
Differentiation Potential ◽  
Histone Deacetylase 1 ◽  
Specific Differentiation ◽  
Induced Pluripotent

Cardiomyocytes derived from embryonic and induced pluripotent stem cells (ES/iPS) provide an excellent source for cell replacement therapies following myocardial ischemia. However, some of the obstacles in the realization of the full potential of iPS/ES cells arise from incomplete and poorly understood molecular mechanisms and epigenetic modifications that govern their cardiovascular specific differentiation. We identified Histone Deacetylase 1 (HDAC1) as a crucial regulator in early differentiation of mES and iPS cells. We propose a novel pathway in which HDAC1 regulates cardiovascular differentiation by regulating SOX17 which in turn regulates BMP2 signaling in differentiating pluripotent cells. Utilizing stable HDAC1 knock-down (HDAC1-KD) cell lines, we report an essential role for HDAC1 in deacetylating regulatory regions of pluripotency-associated genes during early cardiovascular differentiation. HDAC1-KD cells show severely repressed cardiomyocyte differentiation potential. We propose a novel HDAC1-BMP2-SOX17 dependent pathway through which deacetylation of pluripotency associated genes leads to their suppression and allows for early cardiovascular-associated genes to be expressed and differentiation to occur. Furthermore, we show that HDAC1 affects DNA methylation both during pluripotency and differentiation and plays a crucial, non-redundant role in cardiovascular specific differentiation and cardiomyocyte maturation. Our data elucidates important differences between ES and iPS HDAC1-KD cells that affect their ability to differentiate into cardiovascular lineages. As varying levels of chromatin modifying enzymes are likely to exist in patient derived iPS cells, understanding the molecular circuitry of these enzymes in ES and iPS cells is critical for their potential therapeutic applications in regenerative medicine. Further research in the molecular mechanisms involved in this process will greatly aid our understanding of the epigenetic circuitry of pluripotency and differentiation in pluripotent cells.

Epigenetics

2019 ◽  
pp. 56-70
Author(s):  
Edward Hookway ◽  
Nicholas Athanasou ◽  
Udo Oppermann
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Tumour Suppressor Genes ◽  
Epigenetic Mechanisms ◽  
Therapeutic Approaches ◽  
Control Of Gene Expression ◽  
Non Coding Rnas ◽  
Epigenetic Processes

Epigenetics is a term that refers to a collection of diverse mechanisms that are important in both the control of gene expression and the transmission of this information during cell division. Epigenetic processes are deranged in many cancers, leading to a combination of inappropriate silencing of tumour suppressor genes and overexpression of oncogenes. In this chapter, the molecular mechanisms that underpin the major epigenetic processes of DNA methylation, histone modification, and non-coding RNAs will be described in both their normal physiological roles and in the context of cancer. The challenge of understanding the complexity of the interactions between different epigenetic mechanisms and the limitations of our current knowledge will be highlighted. Therapeutic approaches towards targeting deranged epigenetic processes will also be described, such as the use of small molecule inhibitors of histone deacetylases.

scholarly journals Perivascular-Derived Mesenchymal Stem Cells

2019 ◽  
Vol 98 (10) ◽  
pp. 1066-1072 ◽  
Author(s):  
V. Yianni ◽  
P.T. Sharpe
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Dental Pulp ◽  
Molecular Mechanisms ◽  
Lineage Tracing ◽  
Specific Gene ◽  
Genetic Lineage ◽  
Differentiation Potential

Cells have been identified in postnatal tissues that, when isolated from multiple mesenchymal compartments, can be stimulated in vitro to give rise to cells that resemble mature mesenchymal phenotypes, such as odontoblasts, osteoblasts, adipocytes, and myoblasts. This has made these adult cells, collectively called mesenchymal stem cells (MSCs), strong candidates for fields such as tissue engineering and regenerative medicine. Based on evidence from in vivo genetic lineage–tracing studies, pericytes have been identified as a source of MSC precursors in vivo in multiple organs, in response to injury or during homeostasis. Questions of intense debate and interest in the field of tissue engineering and regenerative studies include the following: 1) Are all pericytes, irrespective of tissue of isolation, equal in their differentiation potential? 2) What are the mechanisms that regulate the differentiation of MSCs? To gain a better understanding of the latter, recent work has utilized ChIP-seq (chromatin immunoprecipitation followed by sequencing) to reconstruct histone landscapes. This indicated that for dental pulp pericytes, the odontoblast-specific gene Dspp was found in a transcriptionally permissive state, while in bone marrow pericytes, the osteoblast-specific gene Runx2 was primed for expression. RNA sequencing has also been utilized to further characterize the 2 pericyte populations, and results highlighted that dental pulp pericytes are already precommitted to an odontoblast fate based on enrichment analysis indicating overrepresentation of key odontogenic genes. Furthermore, ChIP-seq analysis of the polycomb repressive complex 1 component RING1B indicated that this complex is likely to be involved in inhibiting inappropriate differentiation, as it localized to a number of loci of key transcription factors that are needed for the induction of adipogenesis, chondrogenesis, or myogenesis. In this review, we highlight recent data elucidating molecular mechanisms that indicate that pericytes can be tissue-specific precommitted MSC precursors in vivo and that this precommitment is a major driving force behind MSC differentiation.

scholarly journals Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

2020 ◽  
Vol 21 (16) ◽  
pp. 5645
Author(s):  
Joseph Wai-Hin Leung ◽  
Kwok-Kuen Cheung ◽  
Shirley Pui-Ching Ngai ◽  
Hector Wing-Hong Tsang ◽  
Benson Wui-Man Lau
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Neurological Diseases ◽  
Protective Effects ◽  
Neurological Outcomes ◽  
Pathological Conditions ◽  
Neurological Illnesses ◽  
Neurological Conditions ◽  
Traditional Understanding

Neurogenesis is the process by which functional new neurons are generated from the neural stem cells (NSCs) or neural progenitor cells (NPCs). Increasing lines of evidence show that neurogenesis impairment is involved in different neurological illnesses, including mood disorders, neurogenerative diseases, and central nervous system (CNS) injuries. Since reversing neurogenesis impairment was found to improve neurological outcomes in the pathological conditions, it is speculated that modulating neurogenesis is a potential therapeutic strategy for neurological diseases. Among different modulators of neurogenesis, melatonin is a particularly interesting one. In traditional understanding, melatonin controls the circadian rhythm and sleep–wake cycle, although it is not directly involved in the proliferation and survival of neurons. In the last decade, it was reported that melatonin plays an important role in the regulation of neurogenesis, and thus it may be a potential treatment for neurogenesis-related disorders. The present review aims to summarize and discuss the recent findings regarding the protective effects of melatonin on the neurogenesis impairment in different neurological conditions. We also address the molecular mechanisms involved in the actions of melatonin in neurogenesis modulation.

scholarly journals Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription

2004 ◽  
Vol 383 (2) ◽  
pp. 393-399 ◽  
Author(s):  
Fabian DOCAGNE ◽  
Cecilia GABRIEL ◽  
Nathalie LEBEURRIER ◽  
Sylvain LESNÉ ◽  
Yannick HOMMET ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Transforming Growth Factor Β ◽  
Precursor Protein ◽  
Transcriptional Level ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

Abnormal deposition of Aβ (amyloid-β peptide) is one of the hallmarks of AD (Alzheimer's disease). This peptide results from the processing and cleavage of its precursor protein, APP (amyloid-β precursor protein). We have demonstrated previously that TGF-β (transforming growth factor-β), which is overexpressed in AD patients, is capable of enhancing the synthesis of APP by astrocytes by a transcriptional mechanism leading to the accumulation of Aβ. In the present study, we aimed at further characterization of the molecular mechanisms sustaining this TGF-β-dependent transcriptional activity. We report the following findings: first, TGF-β is capable of inducing the transcriptional activity of a reporter gene construct corresponding to the +54/+74 region of the APP promoter, named APPTRE (APP TGF-β-responsive element); secondly, although this effect is mediated by a transduction pathway involving Smad3 (signalling mother against decapentaplegic peptide 3) and Smad4, Smad2 or other Smads failed to induce the activity of APPTRE. We also observed that the APPTRE sequence not only responds to the Smad3 transcription factor, but also the Sp1 (signal protein 1) transcription factor co-operates with Smads to potentiate the TGF-β-dependent activation of APP. TGF-β signalling induces the formation of nuclear complexes composed of Sp1, Smad3 and Smad4. Overall, the present study gives new insights for a better understanding of the fine molecular mechanisms occurring at the transcriptional level and regulating TGF-β-dependent transcription. In the context of AD, our results provide additional evidence for a key role for TGF-β in the regulation of Aβ production.

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