scholarly journals Ott1 (Rbm15) Is Essential for Placental Vascular Branching Morphogenesis and Embryonic Development of the Heart and Spleen

2008 ◽  
Vol 29 (2) ◽  
pp. 333-341 ◽  
Author(s):  
Glen D. Raffel ◽  
Gerald C. Chu ◽  
Jonathan L. Jesneck ◽  
Dana E. Cullen ◽  
Roderick T. Bronson ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Cardiac Development ◽  
Germ Line ◽  
Global Gene Expression ◽  
Branching Morphogenesis ◽  
Conditional Allele ◽  
Recognition Motifs ◽  
Regulatory Effects ◽  
Incomplete Closure ◽  
Vascular Branching

ABSTRACT The infant leukemia-associated gene Ott1 (Rbm15) has broad regulatory effects within murine hematopoiesis. However, germ line Ott1 deletion results in fetal demise prior to embryonic day 10.5, indicating additional developmental requirements for Ott1. The spen gene family, to which Ott1 belongs, has a transcriptional activation/repression domain and RNA recognition motifs and has a significant role in the development of the head and thorax in Drosophila melanogaster. Early Ott1-deficient embryos show growth retardation and incomplete closure of the notochord. Further analysis demonstrated placental defects in the spongiotrophoblast and syncytiotrophoblast layers, resulting in an arrest of vascular branching morphogenesis. The rescue of the placental defect using a conditional allele with a trophoblast-sparing cre transgene allowed embryos to form a normal placenta and survive gestation. This outcome showed that the process of vascular branching morphogenesis in Ott1-deficient animals was regulated by the trophoblast compartment rather than the fetal vasculature. Mice surviving to term manifested hyposplenia and abnormal cardiac development. Analysis of global gene expression of Ott1-deficient embryonic hearts showed an enrichment of hypoxia-related genes and a significant alteration of several candidate genes critical for cardiac development. Thus, Ott1-dependent pathways, in addition to being implicated in leukemogenesis, may also be important for the pathogenesis of placental insufficiency and cardiac malformations.

Developmental stage- and spermatogenic cycle-specific expression of transcription factor GATA-1 in mouse Sertoli cells

Development ◽  
1994 ◽  
Vol 120 (7) ◽  
pp. 1759-1766 ◽  
Author(s):  
K. Yomogida ◽  
H. Ohtani ◽  
H. Harigae ◽  
E. Ito ◽  
Y. Nishimune ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Developmental Stage ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Sertoli Cells ◽  
Transcriptional Activation ◽  
Germ Line ◽  
Mouse Testis ◽  
Seminiferous Tubules ◽  
Specific Expression

GATA-1 is an essential factor for the transcriptional activation of erythroid-specific genes, and is also abundantly expressed in a discrete subset of cells bordering the seminiferous epithelium in tubules of the murine testis. In examining normal and germ-line defective mutant mice, we show here that GATA-1 is expressed only in the Sertoli cell lineage in mouse testis. GATA-1 expression in Sertoli cells is induced concomitantly with the first wave of spermatogenesis, and GATA-1-positive cells are uniformly distributed among all tubules during prepubertal testis development. However, the number of GATA-1-positive cells declines thereafter and were found only in the peripheral zone of seminiferous tubules in stages VII, VIII and IX of spermatogenesis in the adult mouse testis. In contrast, virtually every Sertoli cell in mutant W/Wv, jsd/jsd or cryptorchid mice (all of which lack significant numbers of germ cells) expresses GATA-1, thus showing that the expression of this transcription factor is negatively controlled by the maturing germ cells. These observations suggest that transcription factor GATA-1 is a developmental stage- and spermatogenic cycle-specific regulator of gene expression in Sertoli cells.

scholarly journals Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus

2019 ◽  
Vol 79 (2) ◽  
pp. 242-253 ◽  
Author(s):  
Maria Grigoriou ◽  
Aggelos Banos ◽  
Anastasia Filia ◽  
Pavlos Pavlidis ◽  
Stavroula Giannouli ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Progenitor Cells ◽  
Immune Cells ◽  
Lupus Erythematosus ◽  
Transcriptional Activation ◽  
Severe Disease ◽  
Enrichment Analysis ◽  
Global Gene Expression ◽  
Systemic Lupus ◽  
Stem And Progenitor Cells

ObjectivesHaematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs.MethodsA global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence.ResultsTranscriptomic analysis of Lin−Sca-1+c-Kit+ haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)—but not of common lymphoid progenitors—reminiscent of a ‘trained immunity’ signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe, Cebpd and Csf3r, and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data.ConclusionsAberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare.Trial registration number4948/19-07-2016.

scholarly journals A MUC5B polymorphism associated with Idiopathic Pulmonary Fibrosis mediates overexpression through decreased CpG methylation and C/EBPβ transcriptional activation

2019 ◽  
Author(s):  
Amaranta U. Armesto-Jimenez ◽  
Ari J. Arason ◽  
Olafur A. Stefansson ◽  
Gunnar Gudmundsson ◽  
Thorarinn Gudjonsson ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transcriptional Activation ◽  
Risk Allele ◽  
Promoter Polymorphism ◽  
Regulatory Factor ◽  
Combined Mechanism ◽  
Regulatory Effects ◽  
Factor C ◽  
Insight Into

AbstractIdiopathic pulmonary fibrosis is a progressive and fatal lung disease of unknown aetiology. The strongest genetic risk factor associated with IPF development is a MUC5B promoter polymorphism (rs35705950). However, the mechanism underlying its effects remains unknown. In this study we have focused on the molecular consequences of the polymorphism on the regulation of MUC5B expression. We have identified a combined mechanism involving both methylation and direct transcriptional regulation mediated by the polymorphic variant on MUC5B overexpression. Our results demonstrate that the minor allele (T) associated with rs35705950 disturbs a DNA methylation site, directly increasing MUC5B expression. Furthermore, this same variant also creates a novel binding site for the transcription factor C/EBPβ leading to transcriptional activation of MUC5B. Our findings provide a novel insight into the regulatory effects of the IPF risk allele, rs35705950 and identifies C/EBPβ as an important regulatory factor in the development of IPF.

scholarly journals Retinal myeloid cells regulate tip cell selection and vascular branching morphogenesis via Notch ligand Delta-like 1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fabian Haupt ◽  
Kashyap Krishnasamy ◽  
L. Christian Napp ◽  
Michael Augustynik ◽  
Anne Limbourg ◽  
...  
Keyword(s):  
Myeloid Cells ◽  
Branching Morphogenesis ◽  
Cell Selection ◽  
Notch Ligand ◽  
Tip Cell ◽  
Vascular Branching

scholarly journals Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4178-4183 ◽  
Author(s):  
Jun J. Yang ◽  
Deepa Bhojwani ◽  
Wenjian Yang ◽  
Xiangjun Cai ◽  
Gabriele Stocco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Molecular Evolution ◽  
Copy Number ◽  
Germ Line ◽  
Lymphoblastic Leukemia ◽  
Global Gene Expression ◽  
Disease Recurrence ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Copy Number Changes

Abstract The underlying pathways that lead to relapse in childhood acute lymphoblastic leukemia (ALL) are unknown. To comprehensively characterize the molecular evolution of relapsed childhood B-precursor ALL, we used human 500K single-nucleotide polymorphism arrays to identify somatic copy number alterations (CNAs) in 20 diagnosis/relapse pairs relative to germ line. We identified 758 CNAs, 66.4% of which were less than 1 Mb, and deletions outnumbered amplifications by approximately 2.5:1. Although CNAs persisting from diagnosis to relapse were observed in all 20 cases, 17 patients exhibited differential CNA patterns from diagnosis to relapse. Of the 396 CNAs observed in 20 relapse samples, only 69 (17.4%) were novel (absent in the matched diagnosis samples). EBF1 and IKZF1 deletions were particularly frequent in this relapsed ALL cohort (25.0% and 35.0%, respectively), suggesting their role in disease recurrence. In addition, we noted concordance in global gene expression and DNA copy number changes (P = 2.2 × 10−16). Finally, relapse-specific focal deletion of MSH6 and, consequently, reduced gene expression were found in 2 of 20 cases. In an independent cohort of children with ALL, reduced expression of MSH6 was associated with resistance to mercaptopurine and prednisone, thereby providing a plausible mechanism by which this acquired deletion contributes to drug resistance at relapse.

scholarly journals The V(D)J recombinational and transcriptional activities of the immunoglobulin heavy-chain intronic enhancer can be mediated through distinct protein-binding sites in a transgenic substrate.

1995 ◽  
Vol 15 (6) ◽  
pp. 3217-3226 ◽  
Author(s):  
C Fernex ◽  
M Capone ◽  
P Ferrier
Keyword(s):  
Heavy Chain ◽  
Transcriptional Activation ◽  
Germ Line ◽  
Receptor Gene ◽  
Immunoglobulin Heavy Chain ◽  
Cell Receptor ◽  
Regulatory Sequences ◽  
Intronic Enhancer ◽  
Molecular Events ◽  
Activation Of Transcription

Immunoglobulin and T-cell receptor gene transcriptional enhancers encompass sequences which stimulate V(D)J recombination of associated variable gene segments. To address the question of whether enhancer-mediated transcriptional activation and recombinational activation depend on the same cis-regulatory sequences, we have produced transgenic mice by using recombination substrates containing various mutations in the immunoglobulin heavy-chain intronic enhancer (E mu). Analysis of substrate rearrangements indicated that specific compound elements including E-box transcriptional motifs are crucial for the recombinational activity of E mu in the developing B and T lymphocytes. In most cases, a faithful correlation between the levels of substrate germ line transcription and recombination was observed. However, some of the E mu mutants which were able to activate transcription of the unrearranged substrate were inefficient in stimulating transgene recombination, implying that the latter function depends on molecular events other than the mere activation of transcription and that both activities can be mediated through distinct regulatory sequences. Together, these results support a model in which lymphoid gene enhancers, in addition to providing docking sites for factors that dictate transcriptional accessibility, must have some specific function(s) for activating V(D)J recombination.

Positive and negative modulation of Jun action by thyroid hormone receptor at a unique AP1 site

1993 ◽  
Vol 13 (5) ◽  
pp. 3042-3049
Author(s):  
G Lopez ◽  
F Schaufele ◽  
P Webb ◽  
J M Holloway ◽  
J D Baxter ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Transcriptional Activation ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Binding Activity ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Plasmid Sequence ◽  
Regulatory Effects

We have characterized the putative AP1 site in the backbone of pUC plasmids and found unique regulatory effects. The site, which mapped to a 19-bp region around nucleotide 37, conferred transcriptional activation by Jun or Jun/Fos that was boosted up to fivefold by unliganded thyroid hormone receptor (TR). Thyroid hormone changed potentiation of the Jun response by TR into repression. Although the plasmid sequence is a near-perfect consensus AP1 site, the perfect consensus AP1 site from the human collagenase promoter did not show the same effects. Deletion of the ligand binding domain of the TR eliminated the ability of the receptor to boost Jun activity, and deletion, mutation, or changes in specificity of the DNA binding domain eliminated both its ability to potentiate Jun activity and repress with hormone. In vitro Jun/Fos complexes bound the operative plasmid fragment, and the presence of TR interfered very little with Jun/Fos binding activity. Protein interaction studies in the absence of DNA showed that TR bound Jun protein in solution either in the presence or in the absence of hormone. These observations suggest a mechanism for synergy and repression by TR through modulation of Jun activity: positive when TR is unliganded, and negative when hormone is bound. They also suggest that the presence of the plasmid element can confound studies of the regulation of linked promoters.

Calpain Function in the Differentiation of Mesenchymal Stem Cells

2002 ◽  
Vol 383 (5) ◽  
pp. 757-764 ◽  
Author(s):  
Yukiko Yajima ◽  
Seiichi Kawashima
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Bone Morphogenetic Proteins ◽  
Transcriptional Activation ◽  
Kinase Inhibitor ◽  
Limited Proteolysis ◽  
Biological Significance ◽  
Cytoskeletal Proteins ◽  
Cellular Functions ◽  
Regulatory Effects

Abstract Calpain is a calciumactivated non lysosomal neutral thiol protease (EC 3.4.22.17) present in a wide variety of eukaryotic cells. Calpain is usually present as an inactive form and is activated by calcium ions and phospholipids. The ability of calpain to alter, by limited proteolysis, the activity or function of numerous cytoskeletal proteins, enzymes, and receptors suggests its involvement in various Ca2+ regulated cellular functions. In this review we focus on the differentiation of mesenchymal stem cells, such as the myoblastic, osteoblastic, chondrocytic, and adipocytic lineages, and the biological significance of calpain in its regulation. Calpain has been implicated in the differentiation of myoblasts through the turnover of glycoproteins. In preosteoblastic cells, calpain is important in mediating the proliferative and prodifferentiating effects of parathyroid hormone and bone morphogenetic proteins. For the differentiation of chondrocytes, calpain is involved in cartilagematrix mineralization. Furthermore, calpain is required for the differentiation of 3T3-L1 preadipocytes into adipocytes, involving the transcriptional activation of the C/EBPα gene and the degradation of the cyclindependent kinase inhibitor p27 during the mitotic clonal expansion phase of adipocyte differentiation. We summarize these regulatory effects of calpain on the differentiation of mesenchymal stem cells and speculate on the function and location of calpain in the differentiation processes.

scholarly journals Comparative Global Gene Expression Profiles of Wild-TypeYersinia pestisCO92 and Its Braun Lipoprotein Mutant at Flea and Human Body Temperatures

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Cristi L. Galindo ◽  
Jian Sha ◽  
Scott T. Moen ◽  
Stacy L. Agar ◽  
Michelle L. Kirtley ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Transcriptional Profiling ◽  
Gene Expression Profiles ◽  
Global Gene Expression ◽  
Mammalian Host ◽  
Metabolic Genes ◽  
Stress Related Genes ◽  
Highly Virulent

Braun/murein lipoprotein (Lpp) is involved in inflammatory responses and septic shock. We previously characterized aΔlppmutant ofYersinia pestisCO92 and found that this mutant was defective in surviving in macrophages and was attenuated in a mouse inhalation model of plague when compared to the highly virulent wild-type (WT) bacterium. We performed global transcriptional profiling of WTY. pestisand itsΔlppmutant using microarrays. The organisms were cultured at 26 and 37 degrees Celsius to simulate the flea vector and mammalian host environments, respectively. Our data revealed vastly different effects oflppmutation on the transcriptomes ofY. pestisgrown at 37 versus26C. While the absence of Lpp resulted mainly in the downregulation of metabolic genes at26C, theY. pestis Δlppmutant cultured at37Cexhibited profound alterations in stress response and virulence genes, compared to WT bacteria. We investigated one of the stress-related genes (htrA) downregulated in theΔlppmutant relative to WTY. pestis. Indeed, complementation of theΔlppmutant with thehtrAgene restored intracellular survival of theY. pestis Δlppmutant. Our results support a role for Lpp inY. pestisadaptation to the host environment, possibly via transcriptional activation ofhtrA.

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