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1.
Front Cell Dev Biol ; 10: 826892, 2022.
Article in English | MEDLINE | ID: mdl-35733854

ABSTRACT

Oogenesis produces functional eggs and is essential for fertility, embryonic development, and reproduction. The zebrafish ovary is an excellent model to study oogenesis in vertebrates, and recent studies have identified multiple regulators in oocyte development through forward genetic screens, as well as reverse genetics by CRISPR mutagenesis. However, many developmental steps in oogenesis, in zebrafish and other species, remain poorly understood, and their underlying mechanisms are unknown. Here, we take a genomic approach to systematically uncover biological activities throughout oogenesis. We performed transcriptomic analysis on five stages of oogenesis, from the onset of oocyte differentiation through Stage III, which precedes oocyte maturation. These transcriptomes revealed thousands of differentially expressed genes across stages of oogenesis. We analyzed trends of gene expression dynamics along oogenesis, as well as their expression in pair-wise comparisons between stages. We determined their functionally enriched terms, identifying uniquely characteristic biological activities in each stage. These data identified two prominent developmental phases in oocyte differentiation and traced the accumulation of maternally deposited embryonic regulator transcripts in the developing oocyte. Our analysis provides the first molecular description for oogenesis in zebrafish, which we deposit online as a resource for the community. Further, the presence of multiple gene paralogs in zebrafish, and the exclusive curation by many bioinformatic tools of the single paralogs present in humans, challenge zebrafish genomic analyses. We offer an approach for converting zebrafish gene name nomenclature to the human nomenclature for supporting genomic analyses generally in zebrafish. Altogether, our work provides a valuable resource as a first step to uncover oogenesis mechanisms and candidate regulators and track accumulating transcripts of maternal regulators of embryonic development.

2.
Eur Surg Res ; 62(1): 18-24, 2021.
Article in English | MEDLINE | ID: mdl-33902043

ABSTRACT

INTRODUCTION: Accumulation of plasma mitochondrial DNA (mtDNA) following severe trauma has been shown to correlate with the development of systemic inflammatory response syndrome (SIRS) and may predict mortality. Our objective was to investigate the relationship between levels of circulatory mtDNA following pancreaticoduodenectomy (PD) and the postoperative course. METHODS: Levels of plasma mtDNA were assessed by real-time PCR of the mitochondrial genes ND1 and COX3 in 23 consecutive patients who underwent PD 1 day prior to surgery, within 8 h after surgery, and on postoperative day (POD)1 and POD5. The abundance of mtDNA was assessed relative to preoperative levels and in relation to parameters reflecting the postoperative clinical course. RESULTS: When pooled for all patients, the circulating mtDNA levels were significantly increased after surgery. However, while a significant (at least >2-fold and up to >20-fold) rise was noted in 11 patients, no change in mtDNA levels was noted in the other 12 following surgery. Postoperative rise in circulating mtDNA was associated with an increased rate of postoperative fever until day 5, decreased hemoglobin and albumin levels, and increased white blood cell counts. These patients also suffered from increased rates of delayed gastric emptying. No significant differences were demonstrated in other postoperative parameters. CONCLUSION: Circulating mtDNA surge is associated with an inflammatory response following PD and may potentially be used as an early marker for postoperative course. Studies of larger patient cohorts are warranted.


Subject(s)
Cell-Free Nucleic Acids , DNA, Mitochondrial/metabolism , Pancreaticoduodenectomy , Anastomosis, Surgical , Biomarkers , Humans , Pancreaticoduodenectomy/adverse effects
3.
Genes Immun ; 20(7): 589-598, 2019 09.
Article in English | MEDLINE | ID: mdl-30880333

ABSTRACT

Myeloid derived suppressor cells (MDSCs) play key roles in cancer development. Accumulation of peripheral-blood MDSCs (PB-MDSCs) corresponds to the progression of various cancers, but provides only a crude indicator. We aimed toward identifying changes in the transcriptional profile of PB-MDSCs in response to tumor growth. CT26 colon cancer cells and B16 melanoma cells (106) were inoculated into peritoneal cavities of BALB/c mice and subcutaneously to C57-black mice, respectively. The circulating levels and global transcriptional patterns of PB CD11b+Ly6g+ MDSCs were assessed in control mice, and 4, 8, and 11 days following tumor cell inoculation. Although a significant accumulation of PB-MDSCs was demonstrated only 11 days following tumor induction, a pronounced transcriptional response was identified already on day 4 while the tumor was ~1 mm in size. Further transcriptional changes correlated with different stages of tumor growth. Key MDSC genes and canonical signaling pathways were activated along tumor progression. This phenomenon was demonstrated in both cancer models, and a consensus set of 817 genes, involved in myeloid cell recruitment and angiogenesis, was identified. The data suggest that the transcriptional signatures of PB-MDSC may serve as markers for tumor progression, as well as providing potential targets for future therapies.


Subject(s)
CD11b Antigen/genetics , Myeloid-Derived Suppressor Cells/metabolism , Animals , CD11b Antigen/analysis , Disease Progression , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Myeloid Cells/metabolism , Myeloid-Derived Suppressor Cells/physiology , Neoplasms/immunology , Transcriptome/genetics
4.
FASEB J ; 33(5): 5967-5978, 2019 05.
Article in English | MEDLINE | ID: mdl-30730772

ABSTRACT

Liver regeneration depends on sequential activation of pathways and cells involving the remaining organ in recovery of mass. Proliferation of parenchyma is dependent on angiogenesis. Understanding liver regeneration-associated neovascularization may be useful for development of clinical interventions. Myeloid-derived suppressor cells (MDSCs) promote tumor angiogenesis and play a role in developmental processes that necessitate rapid vascularization. We therefore hypothesized that the MDSCs could play a role in liver regeneration. Following partial hepatectomy, MDSCs were enriched within regenerating livers, and their depletion led to increased liver injury and postoperative mortality, reduced liver weights, decreased hepatic vascularization, reduced hepatocyte hypertrophy and proliferation, and aberrant liver function. Gene expression profiling of regenerating liver-derived MDSCs demonstrated a large-scale transcriptional response involving key pathways related to angiogenesis. Functionally, enhanced reactive oxygen species production and angiogenic capacities of regenerating liver-derived MDSCs were confirmed. A comparative analysis revealed that the transcriptional response of MDSCs during liver regeneration resembled that of peripheral blood MDSCs during progression of abdominal tumors, suggesting a common MDSC gene expression profile promoting angiogenesis. In summary, our study shows that MDSCs contribute to early stages of liver regeneration possibly by exerting proangiogenic functions using a unique transcriptional program.-Nachmany, I., Bogoch, Y., Sivan, A., Amar, O., Bondar, E., Zohar, N., Yakubovsky, O., Fainaru, O., Klausner, J. M., Pencovich, N. CD11b+Ly6G+ myeloid-derived suppressor cells promote liver regeneration in a murine model of major hepatectomy.


Subject(s)
Hepatectomy , Liver Regeneration , Myeloid-Derived Suppressor Cells/cytology , Animals , Antigens, Ly/metabolism , CD11b Antigen/metabolism , Cell Line, Tumor , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation , Liver/surgery , Male , Mice , Mice, Inbred BALB C , Myeloid Cells/cytology , Neovascularization, Pathologic , Reactive Oxygen Species/metabolism
5.
Tumour Biol ; 39(4): 1010428317698357, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28443460

ABSTRACT

Glioblastoma multiforme is the most common and aggressive primary brain tumor in adults. A mesenchymal phenotype was associated with tumor aggressiveness and poor prognosis in glioblastoma multiforme patients. Recently, the transcription factor RUNX1 was suggested as a driver of the glioblastoma multiforme mesenchymal gene expression signature; however, its independent role in this process is yet to be described. Here, we assessed the role of RUNX1 in U87 glioblastoma multiforme cells in correspondence to its mediated transcriptome and genome-wide occupancy pattern. Overexpression of RUNX1 led to diminished tumor growth in nude and severe combined immunodeficiency mouse xenograft tumor model. At the molecular level, RUNX1 occupied thousands of genomic regions and regulated the expression of hundreds of target genes, both directly and indirectly. RUNX1 occupied genomic regions that corresponded to genes that were shown to play a role in brain tumor progression and angiogenesis and upon overexpression led to a substantial down-regulation of their expression level. When overexpressed in U87 glioblastoma multiforme cells, RUNX1 down-regulated key pathways in glioblastoma multiforme progression including epithelial to mesenchymal transition, MTORC1 signaling, hypoxia-induced signaling, and TNFa signaling via NFkB. Moreover, master regulators of the glioblastoma multiforme mesenchymal phenotype including CEBPb, ZNF238, and FOSL2 were directly regulated by RUNX1. The data suggest a central role for RUNX1 as master regulator of gene expression in the U87 glioblastoma multiforme cell line and mark RUNX1 as a potential target for novel future therapies for glioblastoma multiforme.


Subject(s)
Cell Proliferation/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Epithelial-Mesenchymal Transition/genetics , Glioblastoma/genetics , Animals , CCAAT-Enhancer-Binding Protein-beta/genetics , Cell Line, Tumor , Core Binding Factor Alpha 2 Subunit/biosynthesis , Fos-Related Antigen-2/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/pathology , Humans , Mice , Repressor Proteins/genetics , Signal Transduction , Xenograft Model Antitumor Assays
6.
OMICS ; 20(3): 139-51, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26983021

ABSTRACT

Postgenomics data are produced in large volumes by life sciences and clinical applications of novel omics diagnostics and therapeutics for precision medicine. To move from "data-to-knowledge-to-innovation," a crucial missing step in the current era is, however, our limited understanding of biological and clinical contexts associated with data. Prominent among the emerging remedies to this challenge are the gene set enrichment tools. This study reports on GeneAnalytics™ ( geneanalytics.genecards.org ), a comprehensive and easy-to-apply gene set analysis tool for rapid contextualization of expression patterns and functional signatures embedded in the postgenomics Big Data domains, such as Next Generation Sequencing (NGS), RNAseq, and microarray experiments. GeneAnalytics' differentiating features include in-depth evidence-based scoring algorithms, an intuitive user interface and proprietary unified data. GeneAnalytics employs the LifeMap Science's GeneCards suite, including the GeneCards®--the human gene database; the MalaCards-the human diseases database; and the PathCards--the biological pathways database. Expression-based analysis in GeneAnalytics relies on the LifeMap Discovery®--the embryonic development and stem cells database, which includes manually curated expression data for normal and diseased tissues, enabling advanced matching algorithm for gene-tissue association. This assists in evaluating differentiation protocols and discovering biomarkers for tissues and cells. Results are directly linked to gene, disease, or cell "cards" in the GeneCards suite. Future developments aim to enhance the GeneAnalytics algorithm as well as visualizations, employing varied graphical display items. Such attributes make GeneAnalytics a broadly applicable postgenomics data analyses and interpretation tool for translation of data to knowledge-based innovation in various Big Data fields such as precision medicine, ecogenomics, nutrigenomics, pharmacogenomics, vaccinomics, and others yet to emerge on the postgenomics horizon.


Subject(s)
Computational Biology/methods , Gene Regulatory Networks , Genome, Human , High-Throughput Nucleotide Sequencing/statistics & numerical data , Microarray Analysis/statistics & numerical data , Software , Algorithms , Data Mining , Databases, Factual , Databases, Genetic , Humans , Metabolic Networks and Pathways/genetics
7.
PLoS One ; 8(7): e66629, 2013.
Article in English | MEDLINE | ID: mdl-23874394

ABSTRACT

LifeMap Discovery™ provides investigators with an integrated database of embryonic development, stem cell biology and regenerative medicine. The hand-curated reconstruction of cell ontology with stem cell biology; including molecular, cellular, anatomical and disease-related information, provides efficient and easy-to-use, searchable research tools. The database collates in vivo and in vitro gene expression and guides translation from in vitro data to the clinical utility, and thus can be utilized as a powerful tool for research and discovery in stem cell biology, developmental biology, disease mechanisms and therapeutic discovery. LifeMap Discovery is freely available to academic nonprofit institutions at http://discovery.lifemapsc.com.


Subject(s)
Embryonic Development , Regenerative Medicine , Animals , Cell Differentiation , Data Mining , Gene Expression , Humans , Protein Biosynthesis , Stem Cells/cytology
8.
Hippocampus ; 21(10): 1114-25, 2011 Oct.
Article in English | MEDLINE | ID: mdl-20623763

ABSTRACT

The study determined whether there were gender differences in the expression of hippocampal genes in adult rats in association with dissimilarity in their behavior, and how these were affected by prenatal stress. Pregnant Wistar rats were subjected to varied stress once daily on days 14-20 of gestation. Adult female offspring of control rats showed significantly less anxiogenic behavior in the elevated plus maze and better discrimination between a novel and familiar object than males in the object recognition test. These gender differences in behavior were markedly attenuated by prenatal stress. Using Affymetrix DNA chip technology on hippocampal extracts prepared from littermates of the offspring used for behavioral tests, we found that 1,680 genes were differentially expressed in control males and females. The gender difference in gene expression was decreased to 11% (191 genes) by prenatal stress. In both sexes, processes like the translational machinery, mitochondrial activity, and cation transport were downregulated compared to controls, but there was a greater suppression of genes involved in vesicle trafficking, regulation of synaptic plasticity, and neurogenesis in females than in males. This was compensated by a higher expression of other components of vesicle trafficking, microtubule-based processes, and neurite development. Prenatal stress decreased the expression of 19 Rab proteins in females and five Rabs in males, but a compensatory increase of Rab partner proteins and effectors only occurred in females. Exposure to stress decreased the expression of synaptic proteins, synaptophysin, and synaptopodin in prenatally stressed males and females and increased those of PSD-95 and NR1 subunit of the N-methyl-D-aspartic acid (NMDA) glutamate receptor only in females. The study provides an unbiased view of key genes and proteins that act as gender dependent molecular sensors. The disruption of their expression by adverse early life stress may explain the alterations that occur in behavior.


Subject(s)
Gene Expression Profiling/statistics & numerical data , Hippocampus/metabolism , Prenatal Exposure Delayed Effects , Sex Characteristics , Stress, Psychological , Synaptic Transmission/physiology , Animals , Disks Large Homolog 4 Protein , Down-Regulation/physiology , Female , Intracellular Signaling Peptides and Proteins/metabolism , Male , Maze Learning/physiology , Membrane Proteins/metabolism , Microfilament Proteins/metabolism , Oligonucleotide Array Sequence Analysis , Pregnancy , Prenatal Exposure Delayed Effects/genetics , Prenatal Exposure Delayed Effects/physiopathology , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism , Recognition, Psychology/physiology , Stress, Psychological/genetics , Stress, Psychological/physiopathology , Synaptophysin , Vesicular Transport Proteins/metabolism , rab GTP-Binding Proteins/metabolism
9.
Fertil Steril ; 89(6): 1641-50, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18163991

ABSTRACT

OBJECTIVE: To examine gene expression profiles of women conceiving spontaneously after the age of 45. DESIGN: Expression profiling by complementary DNA microarray analysis. SETTING: University departments. PATIENT(S): Eight women 45 years or older (study group) who conceived spontaneously and were 6 months after their last delivery were compared with six women aged 45 years old (control group) who had their last delivery before the age of 30. INTERVENTION(S): Blood samples were collected from each woman for RNA isolation from peripheral blood mononuclear cells (PBMC). MAIN OUTCOME MEASURE(S): Expression profiles of PBMC isolated from each woman were determined by using Affymetrix DNA microarray analysis covering about 15,000 identified genes. RESULT(S): Microarray of global gene expression revealed 671 genes that showed statistically significant differential expression between the study and control groups: 383 genes were overexpressed and 288 were underexpressed. The most significant functional groups defining these genes were: apoptosis, ubiquitination, and energy production. As many as 60 genes also participated in ovarian physiology. CONCLUSION(S): These observations suggest that extended fertility is associated with a unique ability to enrich cellular processes, leading to delayed ovarian senescence.


Subject(s)
Gene Expression Profiling , Gene Expression Regulation , Gene Expression , Maternal Age , Aging/genetics , Apoptosis/genetics , Delivery, Obstetric , Energy Metabolism/genetics , Female , Fertility/physiology , Humans , Middle Aged , Oligonucleotide Array Sequence Analysis , Ovary/physiology , Pregnancy , RNA/genetics , Ubiquitin/genetics
10.
Exp Cell Res ; 314(4): 677-90, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18201697

ABSTRACT

The embryonal carcinoma P19 cells provide a model to study neuronal differentiation. Cells that are exposed to retinoic acid become mature neurons within a few days with a pronounced axonal and dendritic polarity. Notably, an accelerated rate of neurite extension characterizes densely but not sparsely plated cells. DNA microarray experiments show maximal differences in gene expression of the dense compared to sparse plated cultures at 18 h after plating. The differentially expressed genes are enriched by functions of cell adhesion and cytoskeletal regulation. Doublecortin, Lis1, Reelin, Map2 and dozens of proteins that regulate cytoskeleton dynamics increase in concordance with a rapid neurite extension. A brief elevation in intracellular cAMP via PKA is sufficient to instigate the phenotype of accelerated neurite extension with no effect on P19 cell fate. Furthermore, we show that the cAMP dependent changes in the expression of cytoskeleton regulators such as doublecortin are restricted to a short time window prior to the establishment of functional neurons. We propose that the wave of gene expression of cytoskeletal regulators that is accompanied by accelerated neurite extension acts in remodeling young developing neurons in the CNS.


Subject(s)
Cytoskeletal Proteins/metabolism , Gene Expression Regulation , Neurites/ultrastructure , Neurons/metabolism , Animals , Carcinoma, Embryonal , Cell Culture Techniques , Cell Differentiation , Cell Line, Tumor , Cell Lineage , Cyclic AMP/metabolism , Cytoskeletal Proteins/genetics , Doublecortin Domain Proteins , Gene Expression Profiling , Mice , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Neurons/cytology , Neuropeptides/genetics , Neuropeptides/metabolism , Reelin Protein
11.
Proteomics ; 7(6): 910-20, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17370269

ABSTRACT

Embryonal carcinoma P19 cells provide an ideal model to study molecular programs along differentiation. Upon induction by retinoic acid (RA), the cells undergo a program of differentiation that generates functioning neurons within 60 h. RA induced cells that were plated as sparse (1000 cells/mm(2)) or dense (4000 cells/mm(2)) cultures showed a marked difference in the culture morphology with the dense cultures exhibiting rapid maturation and accelerated neurite outgrowth. The protein expression levels of the sparse and dense cultures were compared 48 h following RA. Cell extracts were separated by 1-DE and 2-DE and differential expression (>four-fold) proteins were identified by MS. Here, we focus on 20 proteins associated with cytoskeletal regulation and stress-dependent protein refolding. The first group includes drebrin, cofilin, alpha-internexin, vimentin, and nestin. Among the proteins in the second group are subunits of the TCP-1, and several chaperones of the Hsp70 and Hsp90 families. We show that coordinated remodeling of the cytoskeleton and modulations in chaperone activity underlie the change in neurite extension rate. Furthermore, a proteomics-based analysis applied on P19 neurons demonstrated pathways underlying neuronal outgrowth, suggesting that a malfunction of such pathways leads to neuropathological conditions.


Subject(s)
Cytoskeleton/metabolism , Neurons/physiology , Protein Folding , Animals , Carcinoma, Embryonal , Cell Differentiation/physiology , Cytoskeletal Proteins/chemistry , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Cytoskeleton/chemistry , Electrophoresis, Gel, Two-Dimensional , Mass Spectrometry , Mice , Molecular Sequence Data , Neurons/cytology , Neurons/drug effects , Tretinoin/pharmacology , Tumor Cells, Cultured
12.
Proc Natl Acad Sci U S A ; 99(5): 3018-23, 2002 Mar 05.
Article in English | MEDLINE | ID: mdl-11867743

ABSTRACT

Early stages of B cell development take place in the bone marrow, resulting in formation of immature B cells, which migrate to the spleen for their final differentiation into mature cells. This final maturation step is essential for B cells to become responsive to antigens and to participate in the immune response. Previously, we showed that the MHC class II chaperone, invariant chain (Ii), controls the differentiation of B cells from the immature to the mature stage. In this study, by generating transgenic mice expressing truncated Ii lacking its luminal domain, we could dissect the chaperonin activity of Ii from its role in B cell maturation. We demonstrate in vivo that Ii N-terminal domain is directly involved in the maturation of B cells and is sufficient to promote B cell differentiation.


Subject(s)
Antigens, Differentiation, B-Lymphocyte/physiology , B-Lymphocytes/cytology , Histocompatibility Antigens Class II/physiology , Molecular Chaperones/physiology , Animals , Antigens, Differentiation, B-Lymphocyte/genetics , CD4-Positive T-Lymphocytes/cytology , Cell Differentiation , Histocompatibility Antigens Class II/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Molecular Chaperones/genetics , Spleen/cytology
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