Dpp signaling thresholds in the dorsal ectoderm of the Drosophila embryo

Development ◽  
2000 ◽  
Vol 127 (15) ◽  
pp. 3305-3312 ◽  
Author(s):  
H.L. Ashe ◽  
M. Mannervik ◽  
M. Levine
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Histone Acetyltransferase ◽  
Cell Types ◽  
Drosophila Embryo ◽  
Present Evidence ◽  
Drosophila Homolog ◽  
Dorsal Ectoderm ◽  
Transgenic Embryos ◽  
Different Cell Types

The dorsal ectoderm of the Drosophila embryo is subdivided into different cell types by an activity gradient of two TGF(β) signaling molecules, Decapentaplegic (Dpp) and Screw (Scw). Patterning responses to this gradient depend on a secreted inhibitor, Short gastrulation (Sog) and a newly identified transcriptional repressor, Brinker (Brk), which are expressed in neurogenic regions that abut the dorsal ectoderm. Here we examine the expression of a number of Dpp target genes in transgenic embryos that contain ectopic stripes of Dpp, Sog and Brk expression. These studies suggest that the Dpp/Scw activity gradient directly specifies at least three distinct thresholds of gene expression in the dorsal ectoderm of gastrulating embryos. Brk was found to repress two target genes, tailup and pannier, that exhibit different limits of expression within the dorsal ectoderm. These results suggest that the Sog inhibitor and Brk repressor work in concert to establish sharp dorsolateral limits of gene expression. We also present evidence that the activation of Dpp/Scw target genes depends on the Drosophila homolog of the CBP histone acetyltransferase.

The Snail repressor positions Notch signaling in the Drosophila embryo

Development ◽  
2002 ◽  
Vol 129 (7) ◽  
pp. 1785-1793 ◽  
Author(s):  
John Cowden ◽  
Michael Levine
Keyword(s):  
Notch Signaling ◽  
Target Genes ◽  
Regulatory Gene ◽  
Ectopic Expression ◽  
Cell Types ◽  
Notch Receptor ◽  
Drosophila Embryo ◽  
Multiple Cell ◽  
Transgenic Embryos ◽  
Neurogenic Ectoderm

The maternal Dorsal nuclear gradient initiates the differentiation of the mesoderm, neurogenic ectoderm and dorsal ectoderm in the precellular Drosophila embryo. Each tissue is subsequently subdivided into multiple cell types during gastrulation. We have investigated the formation of the mesectoderm within the ventral-most region of the neurogenic ectoderm. Previous studies suggest that the Dorsal gradient works in concert with Notch signaling to specify the mesectoderm through the activation of the regulatory gene sim within single lines of cells that straddle the presumptive mesoderm. This model was confirmed by misexpressing a constitutively activated form of the Notch receptor, NotchIC, in transgenic embryos using the eve stripe2 enhancer. The NotchIC stripe induces ectopic expression of sim in the neurogenic ectoderm where there are low levels of the Dorsal gradient. sim is not activated in the ventral mesoderm, due to inhibition by the localized zinc-finger Snail repressor, which is selectively expressed in the ventral mesoderm. Additional studies suggest that the Snail repressor can also stimulate Notch signaling. A stripe2-snail transgene appears to induce Notch signaling in ‘naïve’ embryos that contain low uniform levels of Dorsal. We suggest that these dual activities of Snail, repression of Notch target genes and stimulation of Notch signaling, help define precise lines of sim expression within the neurogenic ectoderm.

scholarly journals Prediction of Drug Efficacy in Colon Cancer Preclinical Models Using a Novel Ranking Method of Gene Expression

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 149
Author(s):  
Justine Fritz ◽  
Olivier Lefebvre ◽  
Aurore Fernandez ◽  
Jordane Schmidt ◽  
Dominique Bagnard
Keyword(s):  
Gene Expression ◽  
Target Gene ◽  
Target Genes ◽  
Drug Efficacy ◽  
Standard Of Care ◽  
Cell Types ◽  
Efficient Treatment ◽  
Tumor Types ◽  
Different Cell Types ◽  
Reference Samples

The presence of stromal cells in tumors is altering the significance of molecular profiling when using standard methods of gene expression quantification. We developed a novel normalization method to rank target gene expression in tumor samples by comparisons with reference samples representing the different cell types found in a tumor. The score for each target gene obtained after normalization, is aimed to be predictive of targeted therapies efficiency. We performed this qPCR analysis on human colorectal cancers to demonstrate the importance of reference samples to obtain accurate data and on a collection of patient-derived xenografted (PDX) colon tumors treated with Cetuximab (anti-EGFR) to demonstrate that the calculated EGFR score is predictive of Cetuximab efficacy. Interestingly, the score allowed to select an efficient treatment in a PDX model refractory to standard of care. This method is opening a novel way to predict targeted therapy efficiency which could be extended to several tumor types, and to unlimited target genes.

Targeting gene expression to the head: the Drosophila orthodenticle gene is a direct target of the Bicoid morphogen

Development ◽  
1998 ◽  
Vol 125 (21) ◽  
pp. 4185-4193 ◽  
Author(s):  
Q. Gao ◽  
R. Finkelstein
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Regulatory Element ◽  
Regulatory Region ◽  
Repeated Sequence ◽  
Drosophila Embryo ◽  
Sequence Motif ◽  
Specific Expression ◽  
Gap Gene

The Bicoid (Bcd) morphogen establishes the head and thorax of the Drosophila embryo. Bcd activates the transcription of identified target genes in the thoracic segments, but its mechanism of action in the head remains poorly understood. It has been proposed that Bcd directly activates the cephalic gap genes, which are the first zygotic genes to be expressed in the head primordium. It has also been suggested that the affinity of Bcd-binding sites in the promoters of Bcd target genes determines the posterior extent of their expression (the Gene X model). However, both these hypotheses remain untested. Here, we show that a small regulatory region upstream of the cephalic gap gene orthodenticle (otd) is sufficient to recapitulate early otd expression in the head primordium. This region contains two control elements, each capable of driving otd-like expression. The first element has consensus Bcd target sites that bind Bcd in vitro and are necessary for head-specific expression. As predicted by the Gene X model, this element has a relatively low affinity for Bcd. Surprisingly, the second regulatory element has no Bcd sites. Instead, it contains a repeated sequence motif similar to a regulatory element found in the promoters of otd-related genes in vertebrates. Our study is the first demonstration that a cephalic gap gene is directly regulated by Bcd. However, it also shows that zygotic gene expression can be targeted to the head primordium without direct Bcd regulation.

scholarly journals HCR-FlowFISH: A flexible CRISPR screening method to identify cis-regulatory elements and their target genes

2020 ◽  
Author(s):  
SK Reilly ◽  
SJ Gosai ◽  
A Gutierrez ◽  
JC Ulirsch ◽  
M Kanai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Screening Method ◽  
Cell Types ◽  
Regulatory Elements ◽  
Hybridization Chain Reaction ◽  
Genome Wide ◽  
Wide Range ◽  
Causal Variants ◽  
Endogenous Loci

AbstractCRISPR screens for cis-regulatory elements (CREs) have shown unprecedented power to endogenously characterize the non-coding genome. To characterize CREs we developed HCR-FlowFISH (Hybridization Chain Reaction Fluorescent In-Situ Hybridization coupled with Flow Cytometry), which directly quantifies native transcripts within their endogenous loci following CRISPR perturbations of regulatory elements, eliminating the need for restrictive phenotypic assays such as growth or transcript-tagging. HCR-FlowFISH accurately quantifies gene expression across a wide range of transcript levels and cell types. We also developed CASA (CRISPR Activity Screen Analysis), a hierarchical Bayesian model to identify and quantify CRE activity. Using >270,000 perturbations, we identified CREs for GATA1, HDAC6, ERP29, LMO2, MEF2C, CD164, NMU, FEN1 and the FADS gene cluster. Our methods detect subtle gene expression changes and identify CREs regulating multiple genes, sometimes at different magnitudes and directions. We demonstrate the power of HCR-FlowFISH to parse genome-wide association signals by nominating causal variants and target genes.

scholarly journals eQTL Catalogue: a compendium of uniformly processed human gene expression and splicing QTLs

2020 ◽  
Author(s):  
Nurlan Kerimov ◽  
James D Hayhurst ◽  
Kateryna Peikova ◽  
Jonathan R Manning ◽  
Peter Walter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Cell Types ◽  
Summary Statistics ◽  
Ensembl Genome Browser ◽  
Cell Type Specific ◽  
Trait Locus ◽  
Rest Api ◽  
Complex Human Traits ◽  
Insight Into

An increasing number of gene expression quantitative trait locus (eQTL) studies have made summary statistics publicly available, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and colocalisation. However, differences between these datasets, in their variants tested, allele codings, and in the transcriptional features quantified, are a barrier to their widespread use. Consequently, target genes for most GWAS signals have still not been identified. Here, we present the eQTL Catalogue (https://www.ebi.ac.uk/eqtl/), a resource which contains quality controlled, uniformly re-computed QTLs from 21 eQTL studies. We find that for matching cell types and tissues, the eQTL effect sizes are highly reproducible between studies, enabling the integrative analysis of these data. Although most cis-eQTLs were shared between most bulk tissues, the analysis of purified cell types identified a greater diversity of cell-type-specific eQTLs, a subset of which also manifested as novel disease colocalisations. Our summary statistics can be downloaded by FTP, accessed via a REST API, and visualised on the Ensembl genome browser. New datasets will continuously be added to the eQTL Catalogue, enabling the systematic interpretation of human GWAS associations across many cell types and tissues.

The somatic-visceral subdivision of the embryonic mesoderm is initiated by dorsal gradient thresholds in Drosophila

Development ◽  
1995 ◽  
Vol 121 (7) ◽  
pp. 2107-2116 ◽  
Author(s):  
K. Maggert ◽  
M. Levine ◽  
M. Frasch
Keyword(s):  
Expression Pattern ◽  
Target Genes ◽  
Substantial Reduction ◽  
Drosophila Embryo ◽  
Germ Layers ◽  
Cardiac Tissues ◽  
Early Drosophila Embryo ◽  
Dorsal Ectoderm ◽  
Lateral Mesoderm

The maternal dorsal regulatory gradient initiates the differentiation of the mesoderm, neuroectoderm and dorsal ectoderm in the early Drosophila embryo. Two primary dorsal target genes, snail (sna) and decapentaplegic (dpp), define the limits of the presumptive mesoderm and dorsal ectoderm, respectively. Normally, the sna expression pattern encompasses 18–20 cells in ventral and ventrolateral regions. Here we show that narrowing the sna pattern results in fewer invaginated cells. As a result, the mesoderm fails to extend into lateral regions so that fewer cells come into contact with dpp-expressing regions of the dorsal ectoderm. This leads to a substantial reduction in visceral and cardiac tissues, consistent with recent studies suggesting that dpp induces lateral mesoderm. These results also suggest that the dorsal regulatory gradient defines the limits of inductive interactions between germ layers after gastrulation. We discuss the parallels between the subdivision of the mesoderm and dorsal ectoderm.

The helix-loop-helix extramacrochaetae protein is required for proper specification of many cell types in the Drosophila embryo

Development ◽  
1994 ◽  
Vol 120 (9) ◽  
pp. 2555-2566 ◽  
Author(s):  
P. Cubas ◽  
J. Modolell ◽  
M. Ruiz-Gomez
Keyword(s):  
Cell Types ◽  
Drosophila Embryo ◽  
Cell Contact ◽  
Cell Recognition ◽  
Cell Specification ◽  
Helix Loop Helix ◽  
Attachment Sites ◽  
Different Cell Types ◽  
Derivatives Of ◽  
Basic Region

The Drosophila Extramacrochaetae protein antagonizes the proneural function of the Achaete and Scute proteins in the generation of the adult fly sensory organs. Extra-macrochaetae sequesters these basic-region-helix-loop-helix transcription factors as heterodimers inefficient for binding to DNA. We show that, during embryonic development, the extramacrochaetae gene is expressed in complex patterns that comprise derivatives of the three embryonic layers. Expression of extramacrochaetae often precedes and accompanies morphogenetic movements. It also occurs at regions of specialized cell-cell contact and/or cell recognition, like the epidermal part of the muscle attachment sites and the differentiating CNS. The insufficiency of extramacrochaetae affects most tissues where it is expressed. The defects suggest faulty specification of different cell types and result in impairment of processes as diverse as cell proliferation and commitment, cell adhesion and cell recognition. If Extramacrochaetae participates in cell specification by dimerizing with basic-region-helix-loop-helix proteins, the variety of defects and tissues affected by the insufficiency of extramacrochaetae suggests that helix-loop-helix proteins are involved in many embryonic developmental processes.

scholarly journals A compendium of uniformly processed human gene expression and splicing quantitative trait loci

2021 ◽  
Vol 53 (9) ◽  
pp. 1290-1299
Author(s):  
Nurlan Kerimov ◽  
James D. Hayhurst ◽  
Kateryna Peikova ◽  
Jonathan R. Manning ◽  
Peter Walter ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantitative Trait ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Cell Types ◽  
Summary Statistics ◽  
Genome Wide ◽  
Cell Type Specific ◽  
Trait Locus ◽  
Complex Human Traits

AbstractMany gene expression quantitative trait locus (eQTL) studies have published their summary statistics, which can be used to gain insight into complex human traits by downstream analyses, such as fine mapping and co-localization. However, technical differences between these datasets are a barrier to their widespread use. Consequently, target genes for most genome-wide association study (GWAS) signals have still not been identified. In the present study, we present the eQTL Catalogue (https://www.ebi.ac.uk/eqtl), a resource of quality-controlled, uniformly re-computed gene expression and splicing QTLs from 21 studies. We find that, for matching cell types and tissues, the eQTL effect sizes are highly reproducible between studies. Although most QTLs were shared between most bulk tissues, we identified a greater diversity of cell-type-specific QTLs from purified cell types, a subset of which also manifested as new disease co-localizations. Our summary statistics are freely available to enable the systematic interpretation of human GWAS associations across many cell types and tissues.

scholarly journals Hypercapnia Regulates Gene Expression and Tissue Function

2020 ◽  
Vol 11 ◽  
Author(s):  
Masahiko Shigemura ◽  
Lynn C. Welch ◽  
Jacob I. Sznajder
Keyword(s):  
Gene Expression ◽  
Lung Diseases ◽  
Transcriptional Response ◽  
Cell Types ◽  
Chronic Lung Diseases ◽  
Tissue Responses ◽  
Mammalian Tissues ◽  
Specific Tissue ◽  
Different Cell Types ◽  
Alveolar Gas Exchange

Carbon dioxide (CO2) is produced in eukaryotic cells primarily during aerobic respiration, resulting in higher CO2 levels in mammalian tissues than those in the atmosphere. CO2 like other gaseous molecules such as oxygen and nitric oxide, is sensed by cells and contributes to cellular and organismal physiology. In humans, elevation of CO2 levels in tissues and the bloodstream (hypercapnia) occurs during impaired alveolar gas exchange in patients with severe acute and chronic lung diseases. Advances in understanding of the biology of high CO2 effects reveal that the changes in CO2 levels are sensed in cells resulting in specific tissue responses. There is accumulating evidence on the transcriptional response to elevated CO2 levels that alters gene expression and activates signaling pathways with consequences for cellular and tissue functions. The nature of hypercapnia-responsive transcriptional regulation is an emerging area of research, as the responses to hypercapnia in different cell types, tissues, and species are not fully understood. Here, we review the current understanding of hypercapnia effects on gene transcription and consequent cellular and tissue functions.

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