scholarly journals Adult fibroblasts retain organ-specific transcriptomic identity

2021 ◽  
Author(s):  
Elvira Forte ◽  
Mirana Ramialison ◽  
Hieu T. Nim ◽  
Madison Mara ◽  
Rachel Cohn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Expression Of Genes ◽  
Essential Components ◽  
Specific Manner ◽  
Organ Specific ◽  
Fibrotic Diseases ◽  
Surrounding Parenchyma ◽  
Different Tissues ◽  
Adult Fibroblasts

Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of interorgan heterogeneity, we compare the gene expression of fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that fibroblasts′ expression of genes typically attributed to the surrounding parenchyma is established in embryonic development and largely maintained in culture, bioengineered tissues, and ectopic transplants. Targeted knockdown of key organ-specific transcription factors affects fibroblasts functions, with modulation of genes related to fibrosis and inflammation. Our data open novel opportunities for the treatment of fibrotic diseases in a more precise, organ-specific manner.

scholarly journals Cold priming uncouples light- and cold-regulation of gene expression in Arabidopsis thaliana

2020 ◽  
Author(s):  
Andras Bittner ◽  
Jörn van Buer ◽  
Margarete Baier
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Plant Pathogens ◽  
Cold Treatment ◽  
Regulation Of Gene Expression ◽  
Light Regulation ◽  
High Light ◽  
Cold Stimulus ◽  
Expression Of Genes ◽  
Specific Manner

Abstract Background: The majority of stress-sensitive genes responds to cold and high light in the same direction, if plants face the stresses for the first time. As shown recently for a small selection of genes of the core environmental stress response cluster, pre-treatment of Arabidopsis thaliana with a 24 h long 4 °C cold stimulus modifies cold regulation of gene expression for up to a week at 20 °C, although the primary cold effects are reverted within the first 24 h. Such memory-based regulation is called priming. Here, we analyse the effect of 24 h cold priming on cold regulation of gene expression on a transcriptome-wide scale and investigate if and how cold priming affects light regulation of gene expression.Results: Cold-priming affected cold and excess light regulation of a small subset of genes. In contrast to the strong gene co-regulation observed upon cold and light stress in not-primed plants, most priming-sensitive genes were regulated in a stressor-specific manner in cold-primed plant. Furthermore, almost as much genes were inversely regulated as co-regulated by a 24 h long 4 °C cold treatment and exposure to heat-filtered high light (800 µmol quanta m-2 s-1). Gene ontology enrichment analysis revealed that cold priming preferentially supports expression of genes involved in the defence against plant pathogens upon cold triggering. The regulation took place on the cost of the expression of genes involved in growth regulation and transport. On the contrary, cold priming resulted in stronger expression of genes regulating metabolism and development and weaker expression of defence genes in response to high light triggering. qPCR with independently cultivated and treated replicates confirmed the trends observed in the RNASeq guide experiment.Conclusion: A 24 h long priming cold stimulus activates a several days lasting stress memory that controls cold and light regulation of gene expression and adjusts growth and defence regulation in a stressor-specific manner.

scholarly journals Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression.

1989 ◽  
Vol 109 (2) ◽  
pp. 877-889 ◽  
Author(s):  
Z Werb ◽  
P M Tremble ◽  
O Behrendtsen ◽  
E Crowley ◽  
C H Damsky
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Monoclonal Antibodies ◽  
Cell Shape ◽  
Degradation Products ◽  
Direct Consequence ◽  
Synovial Fibroblasts ◽  
Fibronectin Receptor ◽  
Expression Of Genes ◽  
Initial Adhesion

We have investigated the effects of ligation of the fibronectin receptor (FnR) on gene expression in rabbit synovial fibroblasts. Monoclonal antibodies to the FnR that block initial adhesion of fibroblasts to fibronectin induced the expression of genes encoding the secreted extracellular matrix-degrading metalloproteinases collagenase and stromelysin. That induction was a direct consequence of interaction with the FnR was shown by the accumulation of mRNA for stromelysin and collagenase. Monoclonal antibodies to several other membrane glycoprotein receptors had no effect on metalloproteinase gene expression. Less than 2 h of treatment of the fibroblasts with anti-FnR in solution was sufficient to trigger the change in gene expression, and induction was blocked by dexamethasone. Unlike other inducers of metalloproteinase expression, including phorbol diesters and growth factors, addition of the anti-FnR in solution to cells adherent to serum-derived adhesion proteins or collagen produced no detectable change in cell shape or actin microfilament organization. Inductive effects were potentiated by cross-linking of the ligand. Fab fragments of anti-FnR were ineffective unless cross-linked or immobilized on the substrate. Adhesion of fibroblasts to native fibronectin did not induce metallo-proteinases. However, adhesion to covalently immobilized peptides containing the arg-gly-asp sequence that were derived from fibronectin, varying in size from hexapeptides up to 120 kD, induced collagenase and stromelysin gene expression. This suggests that degradation products of fibronectin are the natural inductive ligands for the FnR. These data demonstrate that signals leading to changes in gene expression are transduced by the FnR, a member of the integrin family of extracellular matrix receptors. The signaling of changes in gene expression by the FnR is distinct from signaling involving cell shape and actin cytoarchitecture. At least two distinct signals are generated: the binding of fibronectin-derived fragments and adhesion-blocking antibodies to the FnR triggers events different from those triggered by binding of the native fibronectin ligand. Because the genes regulated by this integrin are for enzymes that degrade the extracellular matrix, these results suggest that information transduced by the binding of various ligands to integrins may orchestrate the expression of genes regulating cell behavior in the extracellular environment.

scholarly journals Using Gene Expression to Study Specialized Metabolism—A Practical Guide

2021 ◽  
Vol 11 ◽  
Author(s):  
Riccardo Delli-Ponti ◽  
Devendra Shivhare ◽  
Marek Mutwil
Keyword(s):  
Gene Expression ◽  
Chemical Compounds ◽  
Cell Types ◽  
Biosynthetic Pathways ◽  
Expression Data ◽  
Specialized Metabolism ◽  
Specialized Metabolites ◽  
Expression Of Genes ◽  
Organ Specific ◽  
User Friendly

Plants produce a vast array of chemical compounds that we use as medicines and flavors, but these compounds’ biosynthetic pathways are still poorly understood. This paucity precludes us from modifying, improving, and mass-producing these specialized metabolites in suitable bioreactors. Many of the specialized metabolites are expressed in a narrow range of organs, tissues, and cell types, suggesting a tight regulation of the responsible biosynthetic pathways. Fortunately, with unprecedented ease of generating gene expression data and with >200,000 publicly available RNA sequencing samples, we are now able to study the expression of genes from hundreds of plant species. This review demonstrates how gene expression can elucidate the biosynthetic pathways by mining organ-specific genes, gene expression clusters, and applying various types of co-expression analyses. To empower biologists to perform these analyses, we showcase these analyses using recently published, user-friendly tools. Finally, we analyze the performance of co-expression networks and show that they are a valuable addition to elucidating multiple the biosynthetic pathways of specialized metabolism.

scholarly journals Cold priming uncouples light- and cold-regulation of gene expression in Arabidopsis thaliana

2020 ◽  
Author(s):  
Andras Bittner ◽  
Jörn van Buer ◽  
Margarete Baier
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Plant Pathogens ◽  
Cold Treatment ◽  
Regulation Of Gene Expression ◽  
Light Regulation ◽  
High Light ◽  
Cold Stimulus ◽  
Expression Of Genes ◽  
Specific Manner

Abstract Background The majority of stress-sensitive genes responds to cold and high light in the same direction, if plants face the stresses for the first time. As shown recently for a small selection of genes of the core environmental stress response cluster, pre-treatment of Arabidopsis thaliana with a 24 h long 4 °C cold stimulus modifies cold regulation of gene expression for up to a week at 20 °C, although the primary cold effects are reverted within the first 24 h. Such memory-based regulation is called priming. Here, we show the effect of 24 h cold priming on cold regulation of gene expression on a transcriptome-wide scale and analyse if and how cold priming affects light regulation of gene expression. Results 304 genes were differently regulated between cold-primed and non-primed plants after a second 24 h long 4 °C cold treatment. After triggering the plants with a heat-filtered high light stimulus (800 µmol quanta m -2 s -1 ), 1011 genes showed priming dependent regulation. Only 32 of the priming-sensitive genes responded similarly to cold and light triggering. The majority of the priming-sensitive genes were regulated in a stressor-specific manner. 29 genes were even inversely regulated by the two triggering stimuli. Cold priming preferentially supported expression of genes involved in the defence against plant pathogens upon cold triggering. The regulation took place on the cost of the expression of genes involved in growth regulation and transport. On the contrary, cold priming resulted in stronger expression of genes regulating metabolism and development and weaker expression of defence genes in response to high light triggering. qPCR of several independently cultivated and treated samples confirmed the trends observed by RNA-Sequencing. Conclusion The 24 h long priming cold stimulus activates a several days lasting stress memory that controls cold and light regulation of gene expression and adjusts growth and defence regulation in a stressor-specific manner.

scholarly journals Cold priming uncouples light- and cold-regulation of gene expression in Arabidopsis thaliana

2020 ◽  
Author(s):  
Andras Bittner ◽  
Jörn van Buer ◽  
Margarete Baier
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Plant Pathogens ◽  
Cold Treatment ◽  
Regulation Of Gene Expression ◽  
Light Regulation ◽  
High Light ◽  
Cold Stimulus ◽  
Expression Of Genes ◽  
Specific Manner

Abstract Background The majority of stress-sensitive genes responds to cold and high light in the same direction, if plants face the stresses for the first time. As shown recently for a small selection of genes of the core environmental stress response cluster, pre-treatment of Arabidopsis thaliana with a 24 h long 4 °C cold stimulus modifies cold regulation of gene expression for up to a week at 20 °C, although the primary cold effects are reverted within the first 24 h. Such memory-based regulation is called priming. Here, we analyse the effect of 24 h cold priming on cold regulation of gene expression on a transcriptome-wide scale and investigate if and how cold priming affects light regulation of gene expression. Results Cold-priming affected cold and excess light regulation of a small subset of genes. In contrast to the strong gene co-regulation observed upon cold and light stress in not-primed plants, most priming-sensitive genes were regulated in a stressor-specific manner in cold-primed plant. Furthermore, almost as much genes were inversely regulated as co-regulated by a 24 h long 4 °C cold treatment and exposure to heat-filtered high light (800 µmol quanta m -2 s -1 ). Gene ontology enrichment analysis revealed that cold priming preferentially supports expression of genes involved in the defence against plant pathogens upon cold triggering. The regulation took place on the cost of the expression of genes involved in growth regulation and transport. On the contrary, cold priming resulted in stronger expression of genes regulating metabolism and development and weaker expression of defence genes in response to high light triggering. qPCR with independently cultivated and treated replicates confirmed the trends observed in the RNASeq guide experiment. Conclusion A 24 h long priming cold stimulus activates a several days lasting stress memory that controls cold and light regulation of gene expression and adjusts growth and defence regulation in a stressor-specific manner.

scholarly journals Cold priming uncouples light- and cold-regulation of gene expression in Arabidopsis thaliana

2020 ◽  
Author(s):  
Andras Bittner ◽  
Jörn van Buer ◽  
Margarete Baier
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Plant Pathogens ◽  
Cold Treatment ◽  
Regulation Of Gene Expression ◽  
Light Regulation ◽  
High Light ◽  
Cold Stimulus ◽  
Expression Of Genes ◽  
Specific Manner

Abstract Background: The majority of stress-sensitive genes responds to cold and high light in the same direction, if plants face the stresses for the first time. As shown recently for a small selection of genes of the core environmental stress response cluster, pre-treatment of Arabidopsis thaliana with a 24 h long 4 °C cold stimulus modifies cold regulation of gene expression for up to a week at 20 °C, although the primary cold effects are reverted within the first 24 h. Such memory-based regulation is called priming. Here, we analyse the effect of 24 h cold priming on cold regulation of gene expression on a transcriptome-wide scale and investigate if and how cold priming affects light regulation of gene expression.Results: Cold-priming affected cold and excess light regulation of a small subset of genes. In contrast to the strong gene co-regulation observed upon cold and light stress in not-primed plants, most priming-sensitive genes were regulated in a stressor-specific manner in cold-primed plant. Furthermore, almost as much genes were inversely regulated as co-regulated by a 24 h long 4 °C cold treatment and exposure to heat-filtered high light (800 µmol quanta m-2 s-1). Gene ontology enrichment analysis revealed that cold priming preferentially supports expression of genes involved in the defence against plant pathogens upon cold triggering. The regulation took place on the cost of the expression of genes involved in growth regulation and transport. On the contrary, cold priming resulted in stronger expression of genes regulating metabolism and development and weaker expression of defence genes in response to high light triggering. qPCR with independently cultivated and treated replicates confirmed the trends observed in the RNASeq guide experiment.Conclusion: A 24 h long priming cold stimulus activates a several days lasting stress memory that controls cold and light regulation of gene expression and adjusts growth and defence regulation in a stressor-specific manner.

scholarly journals POS0423 NCOA3 AMPLIFIES PROFIBROTIC TRANSCRIPTIONAL PROGRAMS IN SYSTEMIC SCLEROSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 440.1-441
Author(s):  
C. Dees ◽  
S. Poetter ◽  
M. Fuchs ◽  
C. Bergmann ◽  
A. E. Matei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Transcription Factor ◽  
Transcription Factors ◽  
In Silico ◽  
Murine Models ◽  
German Research Foundation ◽  
Binding Motifs ◽  
German Research ◽  
Fibrotic Diseases

Background:Excessive activation of fibroblasts with a TGFβ-biased gene signature and deposition of extracellular matrix are key features of fibrotic diseases. The mechanisms underlying these transcriptional changes remain poorly understood. Deregulation, mutations and malfunctions of transcriptional co-regulators, which can interact with multiple transcription factors and enable a broad-spectrum regulation of transcriptional networks, have been implicated as driving factors in a large number of diseases and pathologies.Objectives:In the present study, we aimed to analyze the role of the co-regulator Nuclear Receptor Co-Activator 3 (NCOA3) in fibroblast activation and tissue fibrosis, and to evaluate a potential interaction of NCOA3 with fibrosis-relevant transcription factors.Methods:NCOA3 was inhibited genetically by siRNA transfection and pharmacologically by the SRC3 inhibitor-2 (SI-2). We performed bulk RNASeq of human dermal fibroblasts and in silico transcription factor binding site screening of differentially expressed genes (DEGs). The interaction of NCOA3 and TGFβ-SMAD signaling was analyzed by reporter and CoIP assays.Results:The expression of NCOA3 in skin biopsies of SSc patients compared to normal controls demonstrated that SSc fibroblasts express modestly, but significantly reduced levels of NCOA3, which persisted in cultured SSc fibroblasts. Stimulation of normal fibroblasts with chronically high levels of TGFβ as they also occur in fibrotic tissue remodeling strongly decreased NCOA3 expression to a similar extent as in SSc fibroblasts. Furthermore, NCOA3 expression is also deregulated in different murine models of skin fibrosis. To investigate the functional effects of decreased NCOA3 levels, we targeted the expression of NCOA3 in normal fibroblasts. SiRNA-mediated knockdown of NCOA3 ameliorated TGFβ-induced gene expression, collagen release, myofibroblast differentiation and cell proliferation. In contrast, knockdown of NCOA3 had no effects on collagen release, expression of contractile proteins or gene expression in unstimulated fibroblasts, suggesting that NCOA3 is not required for cellular homeostasis. To characterize the molecular mechanisms, we performed RNASeq upon NCOA3 knockdown. We identified 343 significant differentially expressed genes (220 downregulated and 123 upregulated with a Benjamini-Hochberg false discovery rate FDR < 0.25 and fold change > 1.5) between TGFβ-stimulated fibroblasts with and without NCOA3 knockdown (NCOA3-DEGs) including the fibrosis-relevant genes EDNRB, COL5A3, HES1, IL11 or IL33. Functional analysis of the NCOA3-DEGs showed enrichment of pathway terms such as collagen binding and extracellular matrix organization. In silico screening of the promoters of the NCOA3-DEGs for potential transcription factor binding motifs revealed binding motifs of core transcription factors of fibroblast activation and tissue fibrosis such as SMAD2/3/4, RBPJ, ZEB1, TCF4, REL, and SNAIL2 amongst the downregulated NCOA3-DEGs. Experimental validation of our biostatistical results using SMAD3 as example demonstrated a higher percentage of NCOA3-pSMAD3 double-positive fibroblasts in skin sections of SSc patients compared to healthy controls. In addition, knockdown of NCOA3 reduced TGFβ-induced SMAD-reporter activity. Furthermore, stimulation with TGFβ increased the interaction of NCOA3 with SMAD3 as analyzed by co-immunoprecipitation. Simultaneous knockdown of NCOA3 and SMAD3 showed no additional reductions compared to the single knockdowns, suggesting that NCOA3 controls SMAD3-dependent gene transcription under fibrotic conditions. Finally, inhibition of NCOA3 showed anti-fibrotic effects in different murine models of experimental skin and lung fibrosis.Conclusion:Our findings characterize NCOA3 as regulator of multiple pro-fibrotic transcription programs. Pharmaceutical inhibition of NCOA3 might be a strategy to interfere simultaneously with several core pro-fibrotic mediators in fibrotic diseases such as SSc.Acknowledgements:We thank Lena Summa, Vladyslav Fedorchenko, Wolfgang Espach and Regina Kleinlein for excellent technical assistance.The study was funded by grants DI 1537/7-1, DI 1537/8-1, DI 1537/9-1 and -2, DI 1537/11-1, DI 1537/12-1, DI 1537/13-1, DI 1537/14-1, DI 1537/17-1, DE 2414/2-1, DE 2414/4-1, and RA 2506/3-1 of the German Research Foundation, SFB CRC1181 (project C01) and SFB TR221/ project number 324392634 (B04) of the German Research Foundation, grants J39, J40 and A64 of the IZKF in Erlangen, grant 2013.056.1 of the Wilhelm-Sander-Foundation, grants 2014_A47, 2014_A248 and 2014_A184 of the Else-Kröner-Fresenius-Foundation, grant 14-12-17-1-Bergmann of the ELAN-Foundation Erlangen, BMBF (Era-Net grant 01KT1801), MASCARA program, TP 2 and a Career Support Award of Medicine of the Ernst Jung Foundation.Disclosure of Interests:Clara Dees: None declared, Sebastian Poetter: None declared, Maximilian Fuchs: None declared, Christina Bergmann: None declared, Alexandru-Emil Matei: None declared, Andrea-Hermina Györfi: None declared, Alina Soare: None declared, Andreas Ramming: None declared, Paolo Ceppi: None declared, Georg Schett: None declared, Meik Kunz: None declared, Jörg H.W. Distler Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB

A unique neurogenomic state emerges after aggressive confrontations in males of the fish Betta splendens

2020 ◽  
Author(s):  
Trieu-Duc Vu ◽  
Yuki Iwasaki ◽  
Kenshiro Oshima ◽  
Masato Nikaido ◽  
Ming-Tzu Chiu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Betta Splendens ◽  
Assessment Process ◽  
Expression Of Genes ◽  
Gradual Loss ◽  
Specific Manner ◽  
Complex Decision Making ◽  
Complex Decision ◽  
The Brain

AbstractTerritorial defense involves frequent aggressive confrontations with competitors, but little is known about how brain-transcriptomic profiles change between individuals competing for territory establishment. Our previous study elucidated that brain-transcriptomic synchronization occurs in a pair-specific manner between two males of the fish Betta splendens during fighting, reflecting a mutual assessment process between them at the level of gene expression. Here we evaluated how the brain-transcriptomic profiles of opponents change immediately after shifting their social status (i.e., the winner/loser has emerged) and 30 min after this shift. We showed that unique and carryover hypotheses can be adapted to this system, in which changes in the expression of certain genes are unique to different fighting stages and in which the expression patterns of certain genes are transiently or persistently changed across all fighting stages. Interestingly, the specificity of the brain-transcriptomic synchronization of a pair during fighting was gradually lost after fighting ceased, because of the decrease in the variance in gene expression across all individuals, leading to the emergence of a basal neurogenomic state. Strikingly, this unique state was more basal than the state that existed in the before-fighting group and resulted in the reduced and consistent expression of genes across all individuals. In spite of the consistent and basal overall gene expression in each individual in this state, expression changes for genes related to metabolism, learning and memory, and autism still differentiated losers from winners. The fighting system using male B. splendens thus provides a promising platform for investigating neurogenomic states of aggression in vertebrates.Author summaryCompetitive interactions involve complex decision-making tasks that are shaped by mutual feedback between participants. When two animals interact, transcriptomes across their brains synchronize in a way that reflects how they assess and predict the other’s fighting ability and react to each other’s decisions. Here, we elucidated the gradual loss of brain-transcriptomic synchrony between interacting opponents after their interaction ceased, leading to the emergence of a basal neurogenomic state, in which the variations in gene expression were reduced to a minimum among all individuals. This basal neurogenomic state shares common characteristics with the hibernation state, which animals adopt to minimize their metabolic rates to cope with harsh environmental conditions. We demonstrated that this unique neurogenomic state, which is newly characterized in the present study, is composed of the expression of a unique set of genes, each of which was presumably minimally required for survival, providing a hypothesis that this state represents the smallest unit of neurogenomic activity for sustaining an active life.

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