scholarly journals Intranuclear trafficking of transcription factors: implications for biological control

2000 ◽  
Vol 113 (14) ◽  
pp. 2527-2533 ◽  
Author(s):  
G.S. Stein ◽  
A.J. van Wijnen ◽  
J.L. Stein ◽  
J.B. Lian ◽  
M. Montecino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Spatial Organization ◽  
Three Dimensional ◽  
Myelogenous Leukemia ◽  
Regulatory Factors ◽  
Acute Myelogenous ◽  
Gene Transcripts ◽  
Targeting Signals ◽  
Discrete Domains

The subnuclear organization of nucleic acids and cognate regulatory factors suggests that there are functional interrelationships between nuclear structure and gene expression. Nuclear proteins that are localized in discrete domains within the nucleus include the leukemia-associated acute myelogenous leukemia (AML) and promyelocytic leukemia (PML) factors, the SC-35 RNA-processing factors, nucleolar proteins and components of both transcriptional and DNA replication complexes. Mechanisms that control the spatial distribution of transcription factors within the three-dimensional context of the nucleus may involve the sorting of regulatory information, as well as contribute to the assembly and activity of sites that support gene expression. Molecular, cellular, genetic and biochemical approaches have identified distinct protein segments, termed intranuclear-targeting signals, that are responsible for directing regulatory factors to specific subnuclear sites. Gene rearrangements that remove or alter intranuclear-targeting signals are prevalent in leukemias and have been linked to altered localization of regulatory factors within the nucleus. These modifications in the intranuclear targeting of transcription factors might abrogate fidelity of gene expression in tumor cells by influencing the spatial organization and/or assembly of machineries involved in the synthesis and processing of gene transcripts.

Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4, and CBP: implications for terminal nephron differentiation

2005 ◽  
Vol 288 (5) ◽  
pp. F899-F909 ◽  
Author(s):  
Zubaida Saifudeen ◽  
Susana Dipp ◽  
Hao Fan ◽  
Samir S. El-Dahr
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Dna Binding ◽  
Spatial Organization ◽  
Kidney Development ◽  
Collecting Duct ◽  
Proximal Promoter ◽  
Bradykinin B2 Receptor ◽  
Nephron Differentiation ◽  
Terminal Nephron

Despite a wealth of knowledge regarding the early steps of epithelial differentiation, little is known about the mechanisms responsible for terminal nephron differentiation. The bradykinin B2 receptor (B2R) regulates renal function and integrity, and its expression is induced during terminal nephron differentiation. This study investigates the transcriptional regulation of the B2R during kidney development. The rat B2R 5′-flanking region has a highly conserved cis-acting enhancer in the proximal promoter consisting of contiguous binding sites for the transcription factors cAMP response element binding protein (CREB), p53, and Krüppel-like factor (KLF-4). The B2R enhancer drives reporter gene expression in inner medullary collecting duct-3 cells but is considerably weaker in other cell types. Site-directed mutagenesis and expression of dominant negative mutants demonstrated the requirement of CREB DNA binding and Ser-133 phosphorylation for optimal enhancer function. Moreover, helical phasing experiments showed that disruption of the spatial organization of the enhancer inhibits B2R promoter activity. Several lines of evidence indicate that cooperative interactions among the three transcription factors occur in vivo during terminal nephron differentiation: 1) CREB, p53, and KLF-4 are coexpressed in B2R-positive differentiating cells; 2) the maturational expression of B2R correlates with CREB/p53/KLF-4 DNA-binding activity; 3) assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation; and 4) CREB and p53 occupancy of the B2R enhancer is cooperative. These results demonstrate that combinatorial interactions among the transcription factors, CREB, p53, and KLF-4, and the coactivator CBP, may be critical for the regulation of B2R gene expression during terminal nephron differentiation.

scholarly journals Evolution Of Acute Myelogenous Leukemia Stem Cell Properties Following Treatment and Progression

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 883-883 ◽  
Author(s):  
TzuChieh Ho ◽  
Mark W LaMere ◽  
Kristen O'Dwyer ◽  
Jason H. Mendler ◽  
Jane L. Liesveld ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Acute Myelogenous Leukemia ◽  
Cell Model ◽  
Phenotypic Diversity ◽  
Hierarchical Organization ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Leukemia Stem Cell ◽  
Acute Myelogenous

Abstract Acute Myelogenous Leukemia (AML) is a disease that clinically evolves over time as many patients who are responsive to therapy upfront acquire resistance to the same agents when applied in the relapse setting. The stem cell model for AML has been invoked to explain primary resistance to standard therapy; the leukemia stem cell (LSC) population representing a therapy-refractory reservoir for relapse. There have been no prospective efforts to formally assess the evolution of the LSC population during patients’ clinical course. We performed a prospective characterization of specimens from a well-defined cohort of patients with AML at diagnosis and relapse to assess the frequency and phenotype of functionally defined LSCs. Methods Primary bone marrow and peripheral blood samples were collected on IRB approved protocols from patients with newly diagnosed AML undergoing induction therapy. Twenty-five patients who relapsed after achieving a complete remission were selected for further study. Screening studies identified seven patients whose pre-therapy samples demonstrated sustained engraftment of NSG mice following transplantation. Pre-therapy and post-relapse LSC frequencies were assessed using xenotransplantation limiting dilution analyses (LDA). We assessed the frequencies of CD45RA, CD32, TIM-3, CD96, CD47, and CD97 expressing populations that have been previously published to possess LSC activity. Functionally validated pre-therapy and post-relapse LSC populations were identified using fluorescent labeled cell sorting and NSG xenotransplantation. LSC activity was confirmed for each population using secondary xenotransplantation. Gene expression analysis of highly enriched LSC populations from pre-therapy and post-relapse samples was performed using ABI TILDA qPCR analyses following pre-amplification. Results We demonstrated by LDA an 8 to 42-fold increase in LSC frequency between diagnosis and relapse in paired primary patient samples. The increase in LSC activity was not associated with an increase in frequency for phenotypically-defined populations previously reported to possess LSC activity. Rather, we found that LSC activity expanded at relapse to immunophenotypic populations of leukemic cells that did not possess LSC activity prior to treatment. Moreover, in all patients, the number of phenotypically distinct LSC populations (as defined by CD34 and CD38 or CD32 and CD38) detectable at relapse was dramatically expanded. Further, while the majority of the LSC populations’ gene expression profile remained stable between diagnosis and relapse, a subset of genes were enriched in defined LSC populations at relapse including IL3-receptor alpha and IL1-RAP, both previously demonstrated to play a role in LSC biology. Conclusions This study is the first to characterize the natural evolution of LSCs in vivo following treatment and relapse. We demonstrate an increase in LSC activity and greatly increased phenotypic diversity of the LSC population, suggesting a loss of hierarchical organization following relapse. These findings demonstrate that treatment of AML patients with conventional chemotherapy regimens can promote quantitative and qualitative expansion of the LSC compartment. Further, the data indicate that surface antigen immune-phenotype is not predictive of function in relapse and suggest a major limitation to efforts targeting specific surface antigens in the relapse setting. Understanding the mechanisms by which LSC expansion occurs and how to target it will likely improve our currently poor treatment options for patients who relapse. Disclosures: Becker: Millenium: Research Funding.

scholarly journals A gene regulatory motif that generates oscillatory or multiway switch outputs

2013 ◽  
Vol 10 (79) ◽  
pp. 20120826 ◽  
Author(s):  
Jasmina Panovska-Griffiths ◽  
Karen M. Page ◽  
James Briscoe
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Spatial Organization ◽  
Formation Mechanisms ◽  
Regulatory Interactions ◽  
Qualitative Dynamics ◽  
Gene Regulatory ◽  
Oscillatory Mechanisms ◽  
Parameter Values ◽  
Natural Way

The pattern of gene expression in a developing tissue determines the spatial organization of cell type generation. We previously defined regulatory interactions between a set of transcription factors that specify the pattern of gene expression in progenitors of different neuronal subtypes of the vertebrate neural tube. These transcription factors form a circuit that acts as a multistate switch, patterning the tissue in response to a gradient of Sonic Hedgehog. Here, by simplifying aspects of the regulatory interactions, we found that the topology of the circuit allows either switch-like or oscillatory behaviour depending on parameter values. The qualitative dynamics appear to be controlled by a simpler sub-circuit, which we term the AC–DC motif. We argue that its topology provides a natural way to implement a multistate gene expression switch and we show that the circuit is readily extendable to produce more distinct stripes of gene expression. Our analysis also suggests that AC–DC motifs could be deployed in tissues patterned by oscillatory mechanisms, thus blurring the distinction between pattern-formation mechanisms relying on temporal oscillations or graded signals. Furthermore, during evolution, mechanisms of gradient interpretation might have arisen from oscillatory circuits, or vice versa.

scholarly journals Spatial organization of different sigma factor activities and c-di-GMP signalling within the three-dimensional landscape of a bacterial biofilm

Open Biology ◽  
2018 ◽  
Vol 8 (8) ◽  
pp. 180066 ◽  
Author(s):  
Gisela Klauck ◽  
Diego O. Serra ◽  
Alexandra Possling ◽  
Regine Hengge
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Stationary Phase ◽  
Sigma Factor ◽  
Spatial Organization ◽  
Expression Patterns ◽  
Three Dimensional ◽  
Biomechanical Properties ◽  
Ribosomal Gene ◽  
Bacterial Biofilm

Bacterial biofilms are large aggregates of cells embedded in an extracellular matrix of self-produced polymers. In macrocolony biofilms of Escherichia coli , this matrix is generated in the upper biofilm layer only and shows a surprisingly complex supracellular architecture. Stratified matrix production follows the vertical nutrient gradient and requires the stationary phase σ S (RpoS) subunit of RNA polymerase and the second messenger c-di-GMP. By visualizing global gene expression patterns with a newly designed fingerprint set of Gfp reporter fusions, our study reveals the spatial order of differential sigma factor activities, stringent control of ribosomal gene expression and c-di-GMP signalling in vertically cryosectioned macrocolony biofilms. Long-range physiological stratification shows a duplication of the growth-to-stationary phase pattern that integrates nutrient and oxygen gradients. In addition, distinct short-range heterogeneity occurs within specific biofilm strata and correlates with visually different zones of the refined matrix architecture. These results introduce a new conceptual framework for the control of biofilm formation and demonstrate that the intriguing extracellular matrix architecture, which determines the emergent physiological and biomechanical properties of biofilms, results from the spatial interplay of global gene regulation and microenvironmental conditions. Overall, mature bacterial macrocolony biofilms thus resemble the highly organized tissues of multicellular organisms.

MmTRA1b/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia

2004 ◽  
Vol 28 (2) ◽  
pp. 149-157 ◽  
Author(s):  
Akihiro Yokoyama ◽  
Takuya Yamashita ◽  
Eisuke Shiozawa ◽  
Atsuko Nagasawa ◽  
Junko Okabe-Kado ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Factor ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Phospholipid Scramblase ◽  
Acute Myelogenous ◽  
Phospholipid Scramblase 1

scholarly journals Integrating long-range regulatory interactions to predict gene expression using graph convolutional neural networks

2020 ◽  
Author(s):  
Jeremy Bigness ◽  
Xavi Loinaz ◽  
Shalin Patel ◽  
Erica Larschan ◽  
Ritambhara Singh
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Histone Modifications ◽  
3D Structure ◽  
Myelogenous Leukemia ◽  
Graph Representation ◽  
Regulatory Factors ◽  
Long Range Interactions ◽  
Genomic Regions ◽  
Predict Gene Expression

Long-range spatial interactions among genomic regions are critical for regulating gene expression and their disruption has been associated with a host of diseases. However, when modeling the effects of regulatory factors on gene expression, most deep learning models either neglect long-range interactions or fail to capture the inherent 3D structure of the underlying biological system. This prevents the field from obtaining a more comprehensive understanding of gene regulation and from fully leveraging the structural information present in the data sets. Here, we propose a graph convolutional neural network (GCNN) framework to integrate measurements probing spatial genomic organization and measurements of local regulatory factors, specifically histone modifications, to predict gene expression. This formulation enables the model to incorporate crucial information about long-range interactions via a natural encoding of spatial interaction relationships into a graph representation. Furthermore, we show that our model is interpretable in terms of the observed biological regulatory factors, highlighting both the histone modifications and the interacting genomic regions that contribute to a gene's predicted expression. We apply our GCNN model to datasets for GM12878 (lymphoblastoid) and K562 (myelogenous leukemia) cell lines and demonstrate its state-of-the-art prediction performance. We also obtain importance scores corresponding to the histone mark features and interacting regions for some exemplar genes and validate them with evidence from the literature. Our model presents a novel setup for predicting gene expression by integrating multimodal datasets.

A Role for IL1RAP in Acute Myelogenous Leukemia Stem Cells Following Treatment and Progression

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4266-4266 ◽  
Author(s):  
Tzu-Chieh Ho ◽  
Craig T Jordan ◽  
Mark W. LaMere ◽  
John M. Ashton ◽  
Kristen O'Dwyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Cell Lines ◽  
Small Molecule ◽  
Acute Myelogenous Leukemia ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Molecule Inhibitor ◽  
Acute Myelogenous ◽  
Pre Treatment

Abstract Background Acute Myelogenous Leukemia (AML) evolves as many patients who are responsive to therapy upfront are resistant to the same agents when applied at relapse. We previously reported the results of our prospective efforts to formally assess the evolution of the leukemia stem cell (LSC) population(s) during patients' clinical courses. We identified a 9-90 fold increase in LSC activity and greatly increased phenotypic diversity of the LSC population. To identify the potential mechanisms underlying these changes we further characterized functionally-defined LSC populations from paired diagnosis and relapse samples. Methods Primary bone marrow and peripheral blood samples were collected on IRB approved protocols from patients with newly diagnosed AML undergoing induction therapy as well as normal donors. Twenty-five patients who relapsed after achieving a complete remission were selected for further study. Screening studies identified seven patients whose pre-therapy samples demonstrated sustained engraftment of NSG mice following transplantation. Transcriptional profiling of highly enriched LSC populations from seven patients was performed using ABI TaqMan® Low Density Array (TLDA) qPCR analyses following pre-amplification using a novel 153 gene expression platform. Protein expression levels of interleukin-1 receptor accessory protein (IL1RAP) on bulk leukemia cells and LSC populations from 25 patients were assessed by flow cytometry. The impact of loss of IL1RAP was assessed using lentiviral based shRNA targeting all IL1RAP isoforms followed by assessment of proliferation, apoptosis, colony forming unit (CFU) activity and NSG engraftment capacity in human cell lines as well as in primary patient samples. Downstream signaling events for IL1RAP were probed using a small molecule inhibitor approach. Results While the majority of the LSC populations' gene expression profile remained stable, twelve genes were differentially expressed between pre-treatment and relapsed LSC populations including IL1RAP. Flow cytometric analyses confirmed that IL1RAP is overexpressed on both bulk leukemia populations as well as LSC populations at diagnosis and relapse in comparison to normal hematopoietic stem cell (HSC) populations. Targeting ILRAP1 using shRNA in both cell lines and primary AML samples resulted in impaired proliferation, increased apoptosis, a marked loss of CFU capacity and impaired NSG engraftment. IL1 signaling is known to involve both the MAPkinase and NFKappB pathways. To determine which pathways are involved in IL1RAP mediated LSC survival, we performed a small molecule inhibitor screen targeting elements in both signaling cascades. Established inhibitors of the NFKappaB pathway resulted in loss in loss of leukemic cell function while MAPK signaling inhibition had minimal to no effect. Conclusions We identified IL1RAP as being overexpressed in both bulk leukemia and functionally defined LSC populations from pre-treatment and relapsed AML samples. Loss of IL1RAP was associated with a marked decline in LSC function. Preliminary studies support a primary role for the NF Kappa B pathway in LSC function. Our findings support a critical role for IL1RAP in LSC function and support its development as a target for AML therapy in both the upfront and relapse setting. Disclosures Wang: Immunogen: Research Funding. Calvi:Fate Therapeutics: Patents & Royalties. Becker:Millenium: Research Funding.

scholarly journals PO-165 Effects of Living-High Training-Low on HIF-1α Transcriptional Regulatory Factors MAPKs mRNA in Gastrocnemius of Rats

2018 ◽  
Vol 1 (4) ◽  
Author(s):  
Sen Huang ◽  
Jianhon Liu ◽  
Zhihong Zhou ◽  
Wentao Lin ◽  
Xiquan Weng
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Mrna Expression ◽  
Control Group ◽  
Regulatory Factors ◽  
Training Groups ◽  
Real Time Quantitative Pcr ◽  
Sd Rats ◽  
Transcriptional Regulatory ◽  
Significant Difference

Objective To evaluate the effects of Living-High Training-Low on HIF-1α transcriptional regulatory factors MAPKs mRNA in gastrocnemius of Rats. Methods After adaptive training, 40 8-weeks-old male SD rats were divided into living-low quiet control group (LC), living-low training-low group (LoLo), living-high quiet control group (HC), living-high training-low group (HiLo). All living-high groups stayed in the environment with 13.6% oxygen concentration, about altitude of 3500 m, for 12h/day. All training groups underwent treadmill training with 35m/min for 1hour/day, 5days/week. 4 weeks later, the gastrocnemius was sampled 24 hours after the last training. The ERK, p38MAPK, JNK and HIF-1α mRNA genes expressions in gastrocnemius were measured by real-time quantitative PCR. Results The gastrocnemius ERK mRNA of HiLo group was significantly higher than LC (P<0.01), LoLo and HC groups (P<0.05). The p38MAPK mRNA of HiLo group was significantly higher than LC and LoLo groups (P<0.01 and P<0.05), and there was no significant difference between HiLo and HC group (P>0.05). The JNK and HIF-1α mRNA of HiLo group were significantly higher than other groups (P<0.01). Conclusions Living-High Training-Low significantly raise ERK、p38MAPK、JNK and HIF-1α gene expression in gastrocnemius of Rats. ERK, p38MAPK and JNK may be one of the transcription factors regulating HIF-1α mRNA expression in Living-High Training-Low in gastrocnemius of Rats.

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