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Major differences in microRNA quantification are platform and sequence dependent

Ester Feldmesser, Dena Leshkowitz, Yisrael Parmet, Shirley Horn-Saban
2012 BMC Proceedings  
doi:10.1186/1753-6561-6-s6-p7 fatcat:tcku4meavzhjtfl3rvrg2m45ki

Dual role of starvation signaling in promoting growth and recovery

Yonat Gurvich, Dena Leshkowitz, Naama Barkai, Jeff Gore
2017 PLoS Biology  
OPEN ACCESS Citation: Gurvich Y, Leshkowitz D, Barkai N (2017) Dual role of starvation signaling in promoting growth and recovery. PLoS Biol 15(12): e2002039.  ... 
doi:10.1371/journal.pbio.2002039 pmid:29236696 pmcid:PMC5728490 fatcat:deiwqw3xhzdybdosfi5ypb73ke

Single-cell molecular and cellular architecture of neurohypophyseal cell types in the adult mouse [article]

Qiyu Chen, Dena Leshkowitz, Janna Blechman, Gil Levkowitz
2019 bioRxiv   pre-print
., Leshkowitz, D., Stainier, D.Y.R., et al. (2018) . Pituicyte cues regulate the development of permeable neuro-vascular interfaces. Dev. Cell 47, 711-726.  ... 
doi:10.1101/744466 fatcat:3gvz6xwctvcabdxkqv2fkpyfyi

Single-cell molecular and cellular architecture of the mouse neurohypophysis

Qiyu Chen, Dena Leshkowitz, Janna Blechman, Gil Levkowitz
2020 eNeuro  
The neurohypophysis (NH), located at the posterior lobe of the pituitary, is a major neuroendocrine tissue, which mediates osmotic balance, blood pressure, reproduction, and lactation by means of releasing the neurohormones oxytocin (OXT) and arginine-vasopressin (AVP) from the brain into the peripheral blood circulation. The major cellular components of the NH are hypothalamic axonal termini, fenestrated endothelia and pituicytes, the resident astroglia. However, despite the physiological
more » ... tance of the NH, the exact molecular signature defining neurohypophyseal cell types and in particular the pituicytes, remains unclear. Using single-cell RNA sequencing (scRNA-Seq), we captured seven distinct cell types in the NH and intermediate lobe (IL) of adult male mouse. We revealed novel pituicyte markers showing higher specificity than previously reported. Bioinformatics analysis demonstrated that pituicyte is an astrocytic cell type whose transcriptome resembles that of tanycyte. Single molecule in situ hybridization revealed spatial organization of the major cell types implying intercellular communications. We present a comprehensive molecular and cellular characterization of neurohypophyseal cell types serving as a valuable resource for further functional research.
doi:10.1523/eneuro.0345-19.2019 pmid:31915267 pmcid:PMC6984808 fatcat:kdtrnqi755gtpo55ztjrtarzem

Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes [article]

Shay hantisteanu, Yosef Dicken, Varda Negreanu, Dalia Goldenberg, Ori Brenner, Dena Leshkowitz, Joseph Lotem, Ditsa Levanon, Yoram Groner
2019 bioRxiv   pre-print
RUNX3 is one of three mammalian Runt-domain transcription factors (TFs) that regulate gene expression in several types of immune cells. Runx3-deficiency in mice is associated with a multitude of defects in the adaptive and innate immunity systems, including the development of early onset colitis. Our study reveals that conditional deletion of Runx3 specifically in mononuclear phagocytes (MNP) (MNPRunx3-/-) but not in T cells, recapitulates the early onset spontaneous colitis seen in Runx3-/-
more » ... e. We show that Runx3 is expressed in colonic MNP, including resident macrophages (RM) and the dendritic cell cDC2 subsets and its loss results in impaired differentiation/maturation of both cell types. At the transcriptome level, loss of Runx3 in RM and cDC2 was associated with upregulation of pro-inflammatory genes similar to those in the early onset IBD murine model of RMIl10r-/-. The impaired RM maturation in the absence of Runx3 was associated with a marked decrease in expression of anti-inflammatory and TGFlower case Greek beta-regulated genes. Similarly, the decreased expression of lower case Greek beta-catenin signaling associated genes in Runx3-deficient cDC2 indicates their impaired differentiation/maturation. Analysis of ChIP-seq data suggests that in both MNP cell types a significant fraction of these differentially expressed genes are high confidence Runx3 directly regulated genes. Interestingly, several of these putative Runx3 target genes harbor SNPs associated with IBD susceptibility in humans. Remarkably, the impaired maturation and pro-inflammatory phenotype of MNP lacking Runx3 was associated with a substantial reduction in the prevalence of colonic lamina propria Foxp3+ regulatory T cells and an increase in IFN lower case Greek gamma-producing CD4+ T cells, underscoring Runx3 critical role in establishing tolerogenic MNP. Together, these data emphasize the dual role of Runx3 in colonic MNP, as a transcriptional repressor of pro-inflammatory genes and an activator of maturation-associated genes including anti-inflammatory genes. Our study highlights the significance of the current MNPRunx3-/- model for understanding of human MNP-associated colitis. It provides new insights into the crucial involvement of Runx3 in intestinal immune tolerance by regulating colonic MNP maturation through TGFlower case Greek betaR signaling and anti-inflammatory functions by IL10R signaling, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans including gastrointestinal tract diseases such as celiac and Crohn disease.
doi:10.1101/742650 fatcat:z4tf2p2dhraofk52dqadnltsnq

UTAP: User-friendly Transcriptome Analysis Pipeline

Refael Kohen, Jonathan Barlev, Gil Hornung, Gil Stelzer, Ester Feldmesser, Kiril Kogan, Marilyn Safran, Dena Leshkowitz
2019 BMC Bioinformatics  
RNA-Seq technology is routinely used to characterize the transcriptome, and to detect gene expression differences among cell types, genotypes and conditions. Advances in short-read sequencing instruments such as Illumina Next-Seq have yielded easy-to-operate machines, with high throughput, at a lower price per base. However, processing this data requires bioinformatics expertise to tailor and execute specific solutions for each type of library preparation. Results: In order to enable fast and
more » ... er-friendly data analysis, we developed an intuitive and scalable transcriptome pipeline that executes the full process, starting from cDNA sequences derived by RNA-Seq [Nat Rev Genet 10:57-63, 2009] and bulk MARS-Seq [Science 343:776-779, 2014] and ending with sets of differentially expressed genes. Output files are placed in structured folders, and results summaries are provided in rich and comprehensive reports, containing dozens of plots, tables and links. Conclusion: Our User-friendly Transcriptome Analysis Pipeline (UTAP) is an open source, web-based intuitive platform available to the biomedical research community, enabling researchers to efficiently and accurately analyse transcriptome sequence data.
doi:10.1186/s12859-019-2728-2 fatcat:6ytquwm2nbgmzntbiknqaluaei

Runx3-mediated Transcriptional Program in Cytotoxic Lymphocytes

Joseph Lotem, Ditsa Levanon, Varda Negreanu, Dena Leshkowitz, Gilgi Friedlander, Yoram Groner, Jose Alberola-Ila
2013 PLoS ONE  
Citation: Lotem J, Levanon D, Negreanu V, Leshkowitz D, Friedlander G, et al. (2013) Runx3-mediated Transcriptional Program in Cytotoxic Lymphocytes. PLoS ONE 8(11): e80467.  ... 
doi:10.1371/journal.pone.0080467 pmid:24236182 pmcid:PMC3827420 fatcat:lurxrzjog5bxblt7zr5xqz72wa

Wheat Hybridization and Polyploidization Results in Deregulation of Small RNAs

Michal Kenan-Eichler, Dena Leshkowitz, Lior Tal, Elad Noor, Cathy Melamed-Bessudo, Moshe Feldman, Avraham A. Levy
2011 Genetics  
Supporting Information http://www.genetics.org/cgi/content/full/genetics.111.128348/DC1 Wheat Hybridization and Polyploidization Results in Deregulation of Small RNAs Michal Kenan-Eichler, Dena Leshkowitz  ... 
doi:10.1534/genetics.111.128348 pmid:21467573 pmcid:PMC3122319 fatcat:fwejqt6ju5hfxkyti4wvytchtu

Redistribution of Meiotic Crossovers Along Wheat Chromosomes by Virus-Induced Gene Silencing

Amir Raz, Tal Dahan-Meir, Cathy Melamed-Bessudo, Dena Leshkowitz, Avraham A. Levy
2021 Frontiers in Plant Science  
Meiotic recombination is the main driver of genetic diversity in wheat breeding. The rate and location of crossover (CO) events are regulated by genetic and epigenetic factors. In wheat, most COs occur in subtelomeric regions but are rare in centromeric and pericentric areas. The aim of this work was to increase COs in both "hot" and "cold" chromosomal locations. We used Virus-Induced gene Silencing (VIGS) to downregulate the expression of recombination-suppressing genes XRCC2 and FANCM and of
more » ... pigenetic maintenance genes MET1 and DDM1 during meiosis. VIGS suppresses genes in a dominant, transient and non-transgenic manner, which is convenient in wheat, a hard-to-transform polyploid. F1 hybrids of a cross between two tetraploid lines whose genome was fully sequenced (wild emmer and durum wheat), were infected with a VIGS vector ∼ 2 weeks before meiosis. Recombination was measured in F2 seedlings derived from F1-infected plants and non-infected controls. We found significant up and down-regulation of CO rates along subtelomeric regions as a result of silencing either MET1, DDM1 or XRCC2 during meiosis. In addition, we found up to 93% increase in COs in XRCC2-VIGS treatment in the pericentric regions of some chromosomes. Silencing FANCM showed no effect on CO. Overall, we show that CO distribution was affected by VIGS treatments rather than the total number of COs which did not change. We conclude that transient silencing of specific genes during meiosis can be used as a simple, fast and non-transgenic strategy to improve breeding abilities in specific chromosomal regions.
doi:10.3389/fpls.2020.635139 pmid:33613593 pmcid:PMC7890124 fatcat:czl3nnzlevctloekgtq5s25u5m

Using Synthetic Mouse Spike-In Transcripts to Evaluate RNA-Seq Analysis Tools

Dena Leshkowitz, Ester Feldmesser, Gilgi Friedlander, Ghil Jona, Elena Ainbinder, Yisrael Parmet, Shirley Horn-Saban, Noam Shomron
2016 PLoS ONE  
One of the key applications of next-generation sequencing (NGS) technologies is RNA-Seq for transcriptome genome-wide analysis. Although multiple studies have evaluated and benchmarked RNA-Seq tools dedicated to gene level analysis, few studies have assessed their effectiveness on the transcript-isoform level. Alternative splicing is a naturally occurring phenomenon in eukaryotes, significantly increasing the biodiversity of proteins that can be encoded by the genome. The aim of this study was
more » ... o assess and compare the ability of the bioinformatics approaches and tools to assemble, quantify and detect differentially expressed transcripts using RNA-Seq data, in a controlled experiment. To this end, in vitro synthesized mouse spike-in control transcripts were added to the total RNA of differentiating mouse embryonic bodies, and their expression patterns were measured. This novel approach was used to assess the accuracy of the tools, as established by comparing the observed results versus the results expected of the mouse controlled spiked-in transcripts. We found that detection of differential expression at the gene level is adequate, yet on the transcript-isoform level, all tools tested lacked accuracy and precision.
doi:10.1371/journal.pone.0153782 pmid:27100792 pmcid:PMC4839710 fatcat:phejxww77jhrdm6yfdgdjelg6e

Pseudo-mutant P53 is a unique phenotype of DNMT3A-mutated pre-leukemia

Amos Tuval, Yardena Brilon, Hadas Azogy, Yoni Moskovitz, Dena Leshkowitz, Tomer M Salame, Mark D Minden, Perry Tal, Varda Rotter, Moshe Oren, Nathali Kaushansky, Liran I Shlush
2022 Haematologica  
Pre-leukemic clones carrying DNMT3A mutations have a selective advantage and an inherent chemo-resistance, however the basis for this phenotype has not been fully elucidated. Mutations affecting the gene TP53 occur in pre-leukemic hematopoietic stem/progenitor cells (preL-HSPCs) and lead to chemo-resistance. Many of these mutations cause a conformational change and some of them were shown to enhance self-renewal capacity of preL-HSPCs. Intriguingly, a misfolded P53 was described in AML blasts
more » ... at do not harbor mutations in TP53, emphasizing the dynamic equilibrium between wild-type (WT) and "pseudo-mutant" conformations of P53. By combining single cell analyses and P53 conformation-specific monoclonal antibodies we studied preL-HSPCs from primary human DNMT3A-mutated AML samples. We found that while leukemic blasts express mainly the WT conformation, in preL-HSPCs the pseudomutant conformation is the dominant. HSPCs from non-leukemic samples expressed both conformations to a similar extent. In a mouse model we found a small subset of HSPCs with a dominant pseudo-mutant P53. This subpopulation was significantly larger among DNMT3AR882H-mutated HSPCs, suggesting that while a pre-leukemic mutation can predispose for P53 misfolding, additional factors are involved as well. Treatment with a short peptide that can shift the dynamic equilibrium favoring the WT conformation of P53, specifically eliminated preL-HSPCs that had dysfunctional canonical P53 pathway activity as reflected by single cell RNA sequencing. Our observations shed light upon a possible targetable P53 dysfunction in human preLHSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.
doi:10.3324/haematol.2021.280329 pmid:35199506 fatcat:vzks7i6bjzggpkknb6zqrwyhjy

Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes

Shay Hantisteanu, Yosef Dicken, Varda Negreanu, Dalia Goldenberg, Ori Brenner, Dena Leshkowitz, Joseph Lotem, Ditsa Levanon, Yoram Groner, Hiroyasu Nakano
2020 PLoS ONE  
Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation. Mechanistically, the resulting MNP subset imbalance leads to up-regulation of pro-inflammatory genes as occurs in IL10R-deficient
more » ... M. In addition, RM and cDC2 display a marked decrease in expression of anti-inflammatory/TGF β-regulated genes and β-catenin signaling associated genes, respectively. MNP transcriptome and ChIP-seq data analysis suggest that a significant fraction of genes affected by Runx3 loss are direct Runx3 targets. Collectively, Runx3 imposes intestinal immune tolerance by regulating maturation of colonic anti-inflammatory MNP, befitting the identification of RUNX3 as a genome-wide associated risk gene for various immune-related diseases in humans, including gastrointestinal tract diseases such as Crohn's disease and celiac.
doi:10.1371/journal.pone.0233044 pmid:32453801 fatcat:rrppbo5x65h4zcmxmssl4fa53i

Pseudo-mutant p53 as a targetable phenotype of DNMT3A-mutated pre-leukemia [article]

Amos Tuval, Yardena Brilon, Hadas Ezogy, Yoni Moskovitz, Tamir Biezuner, Dena Leshkowitz, Tomer Meir Salame, Mark D Minden, Perry Tal, Varda Rotter, Moshe Oren, Nathali Kaushansky (+1 others)
2021 bioRxiv   pre-print
Pre-leukemic clones carrying DNMT3A mutations have a selective advantage and an inherent chemo-resistance, however the basis for this phenotype has not been fully elucidated. Mutations affecting the gene TP53 occur in pre-leukemic hematopoietic stem/progenitor cells (preL-HSPCs) and lead to chemo-resistance. Many of these mutations cause a conformational change and some of them were shown to enhance self-renewal capacity of preL-HSPCs. Intriguingly, a misfolded p53 was described in AML blasts
more » ... at do not harbor mutations in TP53, emphasizing the dynamic equilibrium between a wild-type (WT) and a pseudo-mutant conformations of p53. By combining single cell analyses and p53 conformation-specific monoclonal antibodies we studied preL-HSPCs from primary human DNMT3A AML samples. We found that while leukemic blasts express mainly the WT conformation, in preL-HSPCs the pseudo-mutant conformation is the dominant. HSPCs from non-leukemic samples expressed both conformations to a similar extent. Treatment with a short peptide that can shift the dynamic equilibrium favoring the WT conformation of p53, specifically eliminated preL-HSPCs that had dysfunctional canonical p53 pathway activity as reflected by single cell RNA sequencing. Our observations shed light upon a possible targetable p53 dysfunction in human preL-HSPCs carrying DNMT3A mutations. This opens new avenues for leukemia prevention.
doi:10.1101/2021.05.30.446347 fatcat:pdn6kvxhzzbz5bjo7nx7gguazi

Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination

Stephanie A. Redmond, Feng Mei, Yael Eshed-Eisenbach, Lindsay A. Osso, Dena Leshkowitz, Yun-An A. Shen, Jeremy N. Kay, Michel Aurrand-Lions, David A. Lyons, Elior Peles, Jonah R. Chan
2016 Neuron  
doi:10.1016/j.neuron.2016.07.021 pmid:27499083 pmcid:PMC4990461 fatcat:zbqzb2wxtffa7bbvpg4bc24h7u

Transcription Factor BETA2 Acts Cooperatively with E2A and PDX1 to Activate the Insulin Gene Promoter

Eitan Glick, Dena Leshkowitz, Michael D. Walker
2000 Journal of Biological Chemistry  
The insulin gene is efficiently expressed only in pancreatic beta cells. Using reverse transcriptase-polymerase chain reaction analysis, we show that insulin mRNA levels are at least 10 5 -fold higher in beta cells than nonbeta cells. To examine the underlying mechanisms, we expressed beta cell transcription factors by transfection of non-beta cells. Separate expression of BETA2, E2A, or PDX1 led to modest (<10-fold) activation of the insulin promoter, whereas co-expression of the three
more » ... produced synergistic, high level activation (160-fold). This level of activity is ϳ25% that observed in transfected beta cell lines. Of the three factors studied, BE-TA2 appears to play a dominant role. Efficient transcription required a C-terminal activation domain of BETA2 and an N-terminal region, which does not function as an independent activation domain. The myogenic basic helix-loop-helix (bHLH) protein MyoD was unable to bind and activate the promoter, even when its DNA binding region was replaced with that of BETA2. Our results demonstrate the central importance of BETA2 in insulin gene transcription and the importance of sequences outside the canonical DNA binding domain in permitting efficient DNA binding and cell-specific activity of the insulin gene promoter.
doi:10.1074/jbc.275.3.2199 pmid:10636926 fatcat:jru2ht7ok5bylpiqbg7v3u5zty
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