scholarly journals Storing memories: the distinct phases of Polycomb-mediated silencing of Arabidopsis FLC

2019 ◽  
Vol 47 (4) ◽  
pp. 1187-1196 ◽  
Author(s):  
Silvia Costa ◽  
Caroline Dean
Keyword(s):  
Target Genes ◽  
Epigenetic Silencing ◽  
Epigenetic Switch ◽  
Cold Temperatures ◽  
Polycomb Repressive Complex 2 ◽  
Sequence Of Events ◽  
Evolutionarily Conserved ◽  
Intron Boundary ◽  
Polycomb Complex

Abstract Polycomb-mediated epigenetic silencing is central to correct growth and development in higher eukaryotes. The evolutionarily conserved Polycomb repressive complex 2 (PRC2) transcriptionally silences target genes through a mechanism requiring the histone modification H3K27me3. However, we still do not fully understand what defines Polycomb targets, how their expression state is switched from epigenetically ON to OFF and how silencing is subsequently maintained through many cell divisions. An excellent system in which to dissect the sequence of events underlying an epigenetic switch is the Arabidopsis FLC locus. Exposure to cold temperatures progressively induces a PRC2-dependent switch in an increasing proportion of cells, through a mechanism that is driven by the local chromatin environment. Temporally distinct phases of this silencing mechanism have been identified. First, the locus is transcriptionally silenced in a process involving cold-induced antisense transcripts; second, nucleation at the first exon/intron boundary of a Polycomb complex containing cold-induced accessory proteins induces a metastable epigenetically silenced state; third, a Polycomb complex with a distinct composition spreads across the locus in a process requiring DNA replication to deliver long-term epigenetic silencing. Detailed understanding from this system is likely to provide mechanistic insights important for epigenetic silencing in eukaryotes generally.

scholarly journals The loss of Ezh2 drives the pathogenesis of myelofibrosis and sensitizes tumor-initiating cells to bromodomain inhibition

2016 ◽  
Vol 213 (8) ◽  
pp. 1459-1477 ◽  
Author(s):  
Goro Sashida ◽  
Changshan Wang ◽  
Takahisa Tomioka ◽  
Motohiko Oshima ◽  
Kazumasa Aoyama ◽  
...  
Keyword(s):  
Target Genes ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Loss Of Function ◽  
Tumor Initiating Cells ◽  
Promoter Regions ◽  
Epigenetic Switch ◽  
Polycomb Repressive Complex 2 ◽  
Conditional Deletion ◽  
Activating Mutation

EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF [PMF]). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 (JAK2V617F) present in patients with PMF. The deletion of Ezh2 in JAK2V617F mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF. The loss of Ezh2 in JAK2V617F hematopoietic cells caused significant reductions in H3K27 trimethylation (H3K27me3) levels, resulting in an epigenetic switch to H3K27 acetylation (H3K27ac). These epigenetic switches were closely associated with the activation of PRC2 target genes including Hmga2, an oncogene implicated in the pathogenesis of PMF. The treatment of JAK2V617F/Ezh2-null mice with a bromodomain inhibitor significantly attenuated H3K27ac levels at the promoter regions of PRC2 targets and down-regulated their expression, leading to the abrogation of MF-initiating cells. Therefore, an EZH2 insufficiency not only cooperated with active JAK2 to induce MF, but also conferred an oncogenic addiction to the H3K27ac modification in MF-initiating cells that was capable of being restored by bromodomain inhibition.

Mindtree: Tryst with the Corporate Control Market

2021 ◽  
pp. 227797792199190
Author(s):  
P. Bala Bhaskaran
Keyword(s):  
Capital Market ◽  
Corporate Control ◽  
Theory And Practice ◽  
Effective Control ◽  
Small Fish ◽  
Market Theory ◽  
Strategic Fit ◽  
Sequence Of Events ◽  
The Capital Market

The case is structured around the takeover of Mindtree Ltd (ML) by Larsen & Toubro Ltd (L&T) in June 2019. ML was founded and nurtured by a group of software professionals. In two decades, it had blossomed into an enterprise with global presence, US$ 1 billion turnover and a unique organizational culture. In a strange sequence of events, more than 20% of ML’s shares landed in L&T’s lap. L&T grabbed this opportunity and ran a systematic campaign to acquire the company. In about 100 days, L&T achieved its objective and got into the driver’s seat. The case traces the evolution of ML from a start-up to a publicly held company with global standing. It examines the circumstances and events leading to L&T getting the initial stake in the company; it examines the acquisition campaign of L&T and the response of the top management of ML. Research Questions Was there a strategic fit between ML and L&T? Were the capital market processes just and fair to all the stakeholders involved in the acquisition? Was L&T fair, prudent and sensitive in the acquisition process? Was Siddhartha loyal and fair to the founders of ML? Link to Theory The theoretical concepts that would enable a better comprehension of the case are: Analysis of strategic fit in M&A situations Capital market: Theory and practice Strategy for corporate control of an enterprise Significance of culture and ecosystem in knowledge organizations Phenomenon Studied Leadership styles relevant at different stages of evolution of an enterprise are different. A leader, at a given point of time, is successful when he is able to match his aspirations with the leadership needs of the enterprise at that point of time. The case can be used to demonstrate this phenomenon. Case Context Context of the case is that of an emerging infotech enterprise, coming under corporate raid and the unfolding capital market processes. The case highlights the shortcomings of the co-founders, leading to their unseating as also the sensitivity of the incoming management in handling the transition. Findings The case demonstrates the ability of the capital market to be fair to all stakeholders ensuring reward for competence and punishment for sloppiness. The case emphasizes the need for co-founders to have an effective strategy for corporate control; only then they could hope to achieve the long-term objectives. The case also illustrates the significance of sensitivity in handling softer issues like people and ecosystem in ensuring long-term success. Discussions At the outset, the case may appear to be that of a big fish swallowing a small fish. But a closer scrutiny would reveal the multiple dimensions of the case. Consider the role of Siddhartha. He seeded the idea of the company; he was a financier to it; he remained an investor in the company longer than most of the founders; when he pulled out, the co-founders could not hold the company together. Neither Siddhartha nor the co-founders had the far-sightedness to consolidate their shareholdings for effective control of the company into the future. This would trigger discussions on the differing roles of technocrats, managers, leaders and founders. Another point worthy of discussion would be: How were the co-founders choosing their leaders? Was it by rotation among themselves, or did they engage a set of criteria to identify an incumbent capable of leading a global company?

scholarly journals Waterlogging-Stress-Responsive LncRNAs, Their Regulatory Relationships with MiRNAs and Target Genes in Cucumber (Cucumis sativus L.)

2021 ◽  
Vol 22 (15) ◽  
pp. 8197
Author(s):  
Kinga Kęska ◽  
Michał Wojciech Szcześniak ◽  
Adela Adamus ◽  
Małgorzata Czernicka
Keyword(s):  
Target Genes ◽  
Recovery Period ◽  
Sufficient Information ◽  
Low Oxygen ◽  
Waterlogging Tolerance ◽  
Cucumis Sativus L ◽  
Waterlogging Stress ◽  
Non Coding Rna

Low oxygen level is a phenomenon often occurring during the cucumber cultivation period. Genes involved in adaptations to stress can be regulated by non-coding RNA. The aim was the identification of long non-coding RNAs (lncRNAs) involved in the response to long-term waterlogging stress in two cucumber haploid lines, i.e., DH2 (waterlogging tolerant—WL-T) and DH4 (waterlogging sensitive—WL-S). Plants, at the juvenile stage, were waterlogged for 7 days (non-primed, 1xH), and after a 14-day recovery period, plants were stressed again for another 7 days (primed, 2xH). Roots were collected for high-throughput RNA sequencing. Implementation of the bioinformatic pipeline made it possible to determine specific lncRNAs for non-primed and primed plants of both accessions, highlighting differential responses to hypoxia stress. In total, 3738 lncRNA molecules were identified. The highest number (1476) of unique lncRNAs was determined for non-primed WL-S plants. Seventy-one lncRNAs were depicted as potentially being involved in acquiring tolerance to hypoxia in cucumber. Understanding the mechanism of gene regulation under long-term waterlogging by lncRNAs and their interactions with miRNAs provides sufficient information in terms of adaptation to the oxygen deprivation in cucumber. To the best of our knowledge, this is the first report concerning the role of lncRNAs in the regulation of long-term waterlogging tolerance by priming application in cucumber.

scholarly journals Emerging multifaceted roles of BAP1 complexes in biological processes

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Aileen Patricia Szczepanski ◽  
Lu Wang
Keyword(s):  
Transcriptional Repression ◽  
Target Genes ◽  
Regulatory Mechanisms ◽  
Biological Processes ◽  
Multiprotein Complex ◽  
Downstream Target ◽  
Evolutionarily Conserved ◽  
Complex Forms ◽  
Polycomb Repressive Complex 1

AbstractHistone H2AK119 mono-ubiquitination (H2AK119Ub) is a relatively abundant histone modification, mainly catalyzed by the Polycomb Repressive Complex 1 (PRC1) to regulate Polycomb-mediated transcriptional repression of downstream target genes. Consequently, H2AK119Ub can also be dynamically reversed by the BAP1 complex, an evolutionarily conserved multiprotein complex that functions as a general transcriptional activator. In previous studies, it has been reported that the BAP1 complex consists of important biological roles in development, metabolism, and cancer. However, identifying the BAP1 complex’s regulatory mechanisms remains to be elucidated due to its various complex forms and its ability to target non-histone substrates. In this review, we will summarize recent findings that have contributed to the diverse functional role of the BAP1 complex and further discuss the potential in targeting BAP1 for therapeutic use.

scholarly journals MODL-16. ABEMACICLIB, A SELECTIVE CDK4/6 INHIBITOR, RESTRICTS GROWTH OF PEDIATRIC GLIAL-LINEAGE TUMORS IN VITRO AND IN VIVO

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii414-iii414
Author(s):  
Muh-Lii Liang ◽  
Tsung-Han Hsieh ◽  
Tai-Tong Wong
Keyword(s):  
Dna Repair ◽  
Therapeutic Strategy ◽  
Target Genes ◽  
Rna Seq ◽  
Downstream Target ◽  
Rb Phosphorylation ◽  
Glial Lineage

Abstract BACKGROUND Glial-lineage tumors constitute a heterogeneous group of neoplasms, comprising gliomas, oligodendrogliomas, and ependymomas, which account for 40%–50% of all pediatric central nervous system tumors. Advances in modern neuro-oncological therapeutics are aimed at improving neoadjuvant chemotherapy and deferring radiotherapy because radiation exposure may cause long-term side effects on the developing brain in young children. Despite aggressive treatment, more than half the high-grade gliomas (pHGGs) and one-third of ependymomas exhibit recurrence within 2 years of initial treatment. METHODS By using integrated bioinformatics and through experimental validation, we found that at least one gene among CCND1, CDK4, and CDK6 was overexpressed in pHGGs and ependymomas. RESULTS The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell cycle–related and DNA repair–related gene expression, which was determined through RNA-seq analysis. The efficiency of abemaciclib was validated in vitro in pHGGs and ependymoma cells and in vivo by using subcutaneously implanted ependymoma cells from patient-derived xenograft (PDX) in mouse models. Abemaciclib demonstrated the suppression of RB phosphorylation, downstream target genes of E2F, G2M checkpoint, and DNA repair, resulting in tumor suppression. CONCLUSION Abemaciclib showed encouraging results in preclinical pediatric glial-lineage tumors models and represented a potential therapeutic strategy for treating challenging tumors in children.

scholarly journals Financial losses for Dutch stakeholders during the 2013 aflatoxin incident in Maize in Europe

2021 ◽  
Author(s):  
M. Focker ◽  
H. J. van der Fels-Klerx ◽  
A. G. J. M. Oude Lansink
Keyword(s):  
The Netherlands ◽  
Uncertain Data ◽  
Feed Industry ◽  
Sequence Of Events ◽  
Bulk Milk ◽  
High Concentrations ◽  
Aflatoxin B ◽  
Financial Losses

AbstractEarly 2013, high concentrations of aflatoxin M1 were found in the bulk milk of a few dairy farms in the Netherlands. These high concentrations were caused by aflatoxin B1 contaminated maize from Eastern Europe that was processed into compound feed, which was fed to dairy cows. Since the contamination was discovered in the downstream stages of the supply chain, multiple countries and parties were involved and recalls of the feed were necessary, resulting into financial losses. The aim of this study was to estimate the direct short-term financial losses related to the 2013 aflatoxin incident for the maize traders, the feed industry, and the dairy sector in the Netherlands. First, the sequence of events of the incident was retrieved. Then, a Monte Carlo simulation model was built to combine the scarce and uncertain data to estimate the direct financial losses for each stakeholder. The estimated total direct financial losses of this incident were estimated to be between 12 and 25 million euros. The largest share, about 60%, of the total losses was endured by the maize traders. About 39% of the total losses were for the feed industry, and less than 1% of the total losses were for the dairy sector. The financial losses estimated in this study should be interpreted cautiously due to limitations associated with the quality of the data used. Furthermore, this incident led to indirect long-term financial effects, identified but not estimated in this study.

scholarly journals Mediator complex subunit Med19 binds directly GATA transcription factors and is required with Med1 for GATA-driven gene regulation in vivo

2020 ◽  
Vol 295 (39) ◽  
pp. 13617-13629
Author(s):  
Clément Immarigeon ◽  
Sandra Bernat-Fabre ◽  
Emmanuelle Guillou ◽  
Alexis Verger ◽  
Elodie Prince ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Direct Interaction ◽  
Mediator Complex ◽  
Loss Of Function ◽  
Transcriptional Responses ◽  
Rna Pol Ii ◽  
Evolutionarily Conserved

The evolutionarily conserved multiprotein Mediator complex (MED) serves as an interface between DNA-bound transcription factors (TFs) and the RNA Pol II machinery. It has been proposed that each TF interacts with a dedicated MED subunit to induce specific transcriptional responses. But are these binary partnerships sufficient to mediate TF functions? We have previously established that the Med1 Mediator subunit serves as a cofactor of GATA TFs in Drosophila, as shown in mammals. Here, we observe mutant phenotype similarities between another subunit, Med19, and the Drosophila GATA TF Pannier (Pnr), suggesting functional interaction. We further show that Med19 physically interacts with the Drosophila GATA TFs, Pnr and Serpent (Srp), in vivo and in vitro through their conserved C-zinc finger domains. Moreover, Med19 loss of function experiments in vivo or in cellulo indicate that it is required for Pnr- and Srp-dependent gene expression, suggesting general GATA cofactor functions. Interestingly, Med19 but not Med1 is critical for the regulation of all tested GATA target genes, implying shared or differential use of MED subunits by GATAs depending on the target gene. Lastly, we show a direct interaction between Med19 and Med1 by GST pulldown experiments indicating privileged contacts between these two subunits of the MED middle module. Together, these findings identify Med19/Med1 as a composite GATA TF interface and suggest that binary MED subunit–TF partnerships are probably oversimplified models. We propose several mechanisms to account for the transcriptional regulation of GATA-targeted genes.

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