scholarly journals Diversification of heart progenitor cells by EGF signaling and differential modulation of ETS protein activity

2017 ◽  
Author(s):  
Benjamin Schwarz ◽  
Dominik Hollfelder ◽  
Katharina Scharf ◽  
Leonie Hartmann ◽  
Ingolf Reim
Keyword(s):  
Specific Gene ◽  
Differential Modulation ◽  
Large Collection ◽  
Protein Activity ◽  
Induced Mutants ◽  
Pericardial Cells ◽  
Direct Target ◽  
Regulatory Model ◽  
Egf Signaling ◽  
Cardiac Patterning

AbstractFor coordinated circulation, vertebrate and invertebrate hearts require stereotyped arrangements of diverse cell populations. This study explores the process of cardiac cell diversification in the Drosophila heart, focusing on the two major cardioblast subpopulations: generic working myocardial cells and inflow valve-forming ostial cardioblasts. By screening a large collection of randomly induced mutants we identified several genes involved in cardiac patterning. Further analysis revealed an unexpected, specific requirement of EGF signaling for the specification of generic cardioblasts and a subset of pericardial cells. We demonstrate that the Tbx20 ortholog Midline acts as a direct target of the EGFR effector Pointed to repress ostial fates. Furthermore, we identified Edl/Mae, an antagonist of the ETS factor Pointed, as a novel cardiac regulator crucial for ostial cardioblast specification. Combining these findings we propose a regulatory model in which the balance between activation of Pointed and its inhibition by Edl controls cardioblast subtype-specific gene expression.

scholarly journals Diversification of heart progenitor cells by EGF signaling and differential modulation of ETS protein activity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Benjamin Schwarz ◽  
Dominik Hollfelder ◽  
Katharina Scharf ◽  
Leonie Hartmann ◽  
Ingolf Reim
Keyword(s):  
Specific Gene ◽  
Differential Modulation ◽  
Large Collection ◽  
Protein Activity ◽  
Induced Mutants ◽  
Pericardial Cells ◽  
Direct Target ◽  
Regulatory Model ◽  
Egf Signaling ◽  
Cardiac Patterning

For coordinated circulation, vertebrate and invertebrate hearts require stereotyped arrangements of diverse cell populations. This study explores the process of cardiac cell diversification in the Drosophila heart, focusing on the two major cardioblast subpopulations: generic working myocardial cells and inflow valve-forming ostial cardioblasts. By screening a large collection of randomly induced mutants, we identified several genes involved in cardiac patterning. Further analysis revealed an unexpected, specific requirement of EGF signaling for the specification of generic cardioblasts and a subset of pericardial cells. We demonstrate that the Tbx20 ortholog Midline acts as a direct target of the EGFR effector Pointed to repress ostial fates. Furthermore, we identified Edl/Mae, an antagonist of the ETS factor Pointed, as a novel cardiac regulator crucial for ostial cardioblast specification. Combining these findings, we propose a regulatory model in which the balance between activation of Pointed and its inhibition by Edl controls cardioblast subtype-specific gene expression.

scholarly journals Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy

2019 ◽  
Author(s):  
Yingxue Fu ◽  
Zihu Guo ◽  
Ziyin Wu ◽  
Liyang Chen ◽  
Yaohua Ma ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Hippocampal Sclerosis ◽  
Coexpression Network ◽  
Specific Gene ◽  
Protein Activity ◽  
New Gene ◽  
Cell Type Specific ◽  
Time Specific ◽  
Level Analysis

AbstractTemporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unknown, which hinders the discovery of effective anti-epileptogenic drugs. In this study, we built a systems-level analytic framework which integrates gene meta-signatures, gene coexpression network and cellular regulatory network to unveil the evolution landscape of epileptogenic process and to identify key regulators that govern the transition between different epileptogenesis stages. The time-specific hippocampal transcriptomic profiles from five independent rodent TLE models were grouped into acute, latent and chronic stages of epileptogenesis, and were utilized for generating stage-specific gene expression signatures. 13 cell-type specific functional modules were identified from the epilepsy-context coexpression network, and five of them were significantly associated with the entire epileptogenic process. By inferring the differential protein activity of gene regulators in each stage, 265 key regulators underlying epileptogenesis were obtained. Among them, 122 regulators were demonstrated being associated with high seizure frequency and/or hippocampal sclerosis in human TLE patients. Importantly, we discovered four new gene regulators (ANXA5, FAM107A, SEPT2 and SPARC) whose upregulation may drive the process of epileptogenesis and further lead to chronic recurrent seizures or hippocampal sclerosis. Our findings provide a landscape of the gene network dynamics underlying epileptogenesis and uncovered candidate regulators that may serve as potential targets for future anti-epileptogenic therapy development.

The Drosophila homeobox genes zfh-1 and even-skipped are required for cardiac-specific differentiation of a numb-dependent lineage decision

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3241-3251 ◽  
Author(s):  
M.T. Su ◽  
M. Fujioka ◽  
T. Goto ◽  
R. Bodmer
Keyword(s):  
Cell Fate ◽  
Heart Development ◽  
Body Wall ◽  
Individual Cell ◽  
Cell Types ◽  
Control Mechanisms ◽  
Pericardial Cells ◽  
Combinatorial Control ◽  
Lineage Decision ◽  
Direct Target

A series of inductive signals are necessary to subdivide the mesoderm in order to allow the formation of the progenitor cells of the heart. Mesoderm-endogenous transcription factors, such as those encoded by twist and tinman, seem to cooperate with these signals to confer correct context and competence for a cardiac cell fate. Additional factors are likely to be required for the appropriate specification of individual cell types within the forming heart. Similar to tinman, the zinc finger- and homeobox-containing gene, zfh-1, is expressed in the early mesoderm and later in the forming heart, suggesting a possible role in heart development. Here, we show that zfh-1 is specifically required for formation of the even-skipped (eve)-expressing subset of pericardial cells (EPCs), without affecting the formation of their siblings, the founders of a dorsal body wall muscle (DA1). In addition to zfh-1, mesodermal eve itself appears to be needed for correct EPC differentiation, possibly as a direct target of zfh-1. Epistasis experiments show that zfh-1 specifies EPC development independently of numb, the lineage gene that controls DA1 founder versus EPC cell fate. We discuss the combinatorial control mechanisms that specify the EPC cell fate in a spatially precise pattern within the embryo.

scholarly journals microRNA-138 modulates cardiac patterning during embryonic development

2008 ◽  
Vol 105 (46) ◽  
pp. 17830-17835 ◽  
Author(s):  
Sarah U. Morton ◽  
Paul J. Scherz ◽  
Kimberly R. Cordes ◽  
Kathryn N. Ivey ◽  
Didier Y. R. Stainier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Embryonic Development ◽  
Expression Patterns ◽  
Acid Synthesis ◽  
Specific Gene ◽  
Protein Activity ◽  
Gene Encoding ◽  
Small Noncoding Rnas ◽  
Discrete Domains

Organ patterning during embryonic development requires precise temporal and spatial regulation of protein activity. microRNAs (miRNAs), small noncoding RNAs that typically inhibit protein expression, are broadly important for proper development, but their individual functions during organogenesis are largely unknown. We report that miR-138 is expressed in specific domains in the zebrafish heart and is required to establish appropriate chamber-specific gene expression patterns. Disruption of miR-138 function led to ventricular expansion of gene expression normally restricted to the atrio-ventricular valve region and, ultimately, to disrupted ventricular cardiomyocyte morphology and cardiac function. Temporal-specific knockdown of miR-138 by antagomiRs showed miR-138 function was required during a discrete developmental window, 24–34 h post-fertilization (hpf). miR-138 functioned partially by repressing the retinoic acid synthesis enzyme, aldehyde dehydrogenase-1a2, in the ventricle. This activity was complemented by miR-138-mediated ventricular repression of the gene encoding versican (cspg2), which was positively regulated by retinoic-acid signaling. Our findings demonstrate that miR-138 helps establish discrete domains of gene expression during cardiac morphogenesis by targeting multiple members of a common pathway, and also establish the use of antagomiRs in fish for temporal knockdown of miRNA function.

scholarly journals The Myc negative autoregulation mechanism requires Myc-Max association and involves the c-myc P2 minimal promoter.

1997 ◽  
Vol 17 (1) ◽  
pp. 100-114 ◽  
Author(s):  
L M Facchini ◽  
S Chen ◽  
W W Marhin ◽  
J N Lear ◽  
L Z Penn
Keyword(s):  
Transcription Initiation ◽  
Leucine Zipper ◽  
Minimal Promoter ◽  
Luciferase Reporter ◽  
Specific Gene ◽  
Cell Type Specificity ◽  
Protein Activity ◽  
Binding Motifs ◽  
Myc Gene ◽  
Negative Autoregulation

Increasing evidence supports an important biological role for Myc in the downregulation of specific gene transcription. Recent studies suggest that c-Myc may suppress promoter activity through proteins of the basal transcription machinery. We have previously reported that Myc protein, in combination with additional cellular factors, suppresses transcription initiation from the c-myc promoter. To characterize the cis components of this Myc negative autoregulation pathway, fragments of the human c-myc promoter were inserted upstream of luciferase reporter genes and assayed for responsiveness to inducible MycER activation in Rat-1 fibroblasts. We found four- to fivefold suppression of a c-myc P2 minimal promoter fragment upon induction of wild-type MycER protein activity, while induction of a mutant MycER protein lacking amino acids 106 to 143 required for Myc autosuppression failed to elicit this response. This assay is physiologically significant, as it reflects Myc autosuppression of the endogenous c-myc gene with regard to kinetics, dose dependency, cell type specificity, and c-Myc functional domains. Analysis of mutations within the P2 minimal promoter indicated that the cis components of Myc autosuppression could not be ascribed to any known protein-binding motifs. In addition, to address the trans factors required for Myc negative autoregulation, we expressed MycEG and MaxEG leucine zipper dimerization mutants in Rat-1 cells and found that Myc-Max heterodimerization is obligatory for Myc autosuppression. Two models for the Myc autosuppression mechanism are discussed.

scholarly journals Notch Controls Multiple Pancreatic Cell Fate Regulators Through Direct Hes1-mediated Repression

2018 ◽  
Author(s):  
Kristian H. de Lichtenberg ◽  
Philip A. Seymour ◽  
Mette C. Jørgensen ◽  
Yung-Hae Kim ◽  
Anne Grapin-Botton ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Specific Gene ◽  
Pancreatic Cell ◽  
Pancreatic Progenitor ◽  
Endocrine Differentiation ◽  
Pancreatic Progenitor Cells ◽  
Genes Encoding ◽  
Direct Target

AbstractNotch signaling and its effector Hes1 regulate multiple cell fate choices in the developing pancreas, but few direct target genes are known. Here we use transcriptome analyses combined with chromatin immunoprecipitation with next-generation sequencing (ChIP-seq) to identify direct target genes of Hes1. ChIP-seq analysis of endogenous Hes1 in 266-6 cells, a model of multipotent pancreatic progenitor cells, revealed high-confidence peaks associated with 354 genes. Among these were genes important for tip/trunk segregation such asPtf1aandNkx6-1, genes involved in endocrine differentiation such asInsm1andDll4, and genes encoding non-pancreatic basic-Helic-Loop-Helix (bHLH) factors such asNeurog2andAscl1. Surprisingly, we find that Hes1 binds a large number of loci previously reported to bind Ptf1a, including a site downstream of theNkx6-1gene. Notably, we find a number of Hes1 bound genes that are upregulated by γ-secretase inhibition in pancreas explants independently ofNeurog3function, including the tip progenitor/acinar genes;Ptf1a, Gata4, Bhlha15, andGfi1. Together, our data suggest that Notch signaling suppress the tip cell fate by Hes1-mediated repression of the tip-specific gene regulatory network module that includes transcriptional regulators such as Ptf1a, Gata4, Mist1, and Gfi1. Our data also uncover new molecular targets of Notch signaling that may be important for controlling cell fate choices in pancreas development.

scholarly journals Gene regulation during late embryogenesis: the RY motif of maturation-specific gene promoters is a direct target of the FUS3 gene product

2000 ◽  
Vol 21 (5) ◽  
pp. 401-408 ◽  
Author(s):  
Wim Reidt ◽  
Thomas Wohlfarth ◽  
Mats Ellerstrom ◽  
andreas Czihal ◽  
Annegret Tewes ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Gene Product ◽  
Specific Gene ◽  
Gene Promoters ◽  
Late Embryogenesis ◽  
Direct Target

scholarly journals Identification of master regulator genes of UV response and their implications for skin carcinogenesis

2018 ◽  
Vol 40 (5) ◽  
pp. 687-694 ◽  
Author(s):  
Yao Shen ◽  
Gabriel Chan ◽  
Michael Xie ◽  
Wangyong Zeng ◽  
Liang Liu
Keyword(s):  
Skin Cancer ◽  
Uv Radiation ◽  
Genome Stability ◽  
Thyroid Hormone Receptor ◽  
Human Keratinocytes ◽  
Selective Inhibition ◽  
Skin Carcinogenesis ◽  
Specific Gene ◽  
Protein Activity ◽  
Skin Cell

AbstractSolar UV radiation is a major environmental risk factor for skin cancer. Despite decades of robust and meritorious investigation, our understanding of the mechanisms underlying UV-induced skin carcinogenesis remain incomplete. We previously performed comprehensive transcriptomic profiling in human keratinocytes following exposure to different UV radiation conditions to generate UV-specific gene expression signatures. In this study, we utilized Virtual Inference of Protein Activity by Enriched Regulon (VIPER), a robust systems biology tool, on UV-specific skin cell gene signatures to identify master regulators (MRs) of UV-induced transcriptomic changes. We identified multiple prominent candidate UV MRs, including forkhead box M1 (FOXM1), thyroid hormone receptor interactor 13 and DNA isomerase II alpha, which play important roles in cell cycle regulation and genome stability. MR protein activity was either activated or suppressed by UV in normal keratinocytes. Intriguingly, many of the UV-suppressed MRs were activated in human skin squamous cell carcinomas (SCCs), highlighting their importance in skin cancer development. We further demonstrated that selective inhibition of FOXM1, whose activity was elevated in SCC cells, was detrimental to SCC cell survival. Taken together, our study uncovered novel UV MRs that can be explored as new therapeutic targets for future skin cancer treatment.

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