scholarly journals Cap analysis of gene expression reveals alternative promoter usage in a rat model of hypertension

2022 ◽  
Vol 5 (4) ◽  
pp. e202101234
Author(s):  
Sonal Dahale ◽  
Jorge Ruiz-Orera ◽  
Jan Silhavy ◽  
Norbert Hübner ◽  
Sebastiaan van Heesch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Left Ventricle ◽  
Rat Model ◽  
Alternative Promoter ◽  
Brown Norway ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Promoter Usage ◽  
Cap Analysis

The role of alternative promoter usage in tissue-specific gene expression has been well established; however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) sequencing from the left ventricle of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, Brown Norway to understand the role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites in the rat left ventricle, including 1,970 novel cardiac transcription start sites. We identified 28 genes with alternative promoter usage between SHR and Brown Norway, which could lead to protein isoforms differing at the amino terminus between two strains and 475 promoter switching events altering the length of the 5′ UTR. We found that the shift in Insr promoter usage was significantly associated with insulin levels and blood pressure within a panel of HXB/BXH recombinant inbred rat strains, suggesting that hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.

scholarly journals Cap analysis of gene expression (CAGE) sequencing reveals alternative promoter usage in complex disease

2021 ◽  
Author(s):  
Sonal Dahale ◽  
Jorge Ruiz-Orera ◽  
Jan Silhavy ◽  
Norbert Hubner ◽  
Sebastiaan van Heesch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Disease ◽  
Complex Diseases ◽  
Alternative Promoter ◽  
Brown Norway ◽  
Specific Gene ◽  
Insulin Receptor Gene ◽  
Promoter Usage ◽  
Cap Analysis

The role of alternative promoter usage in tissue specific gene expression has been well established, however, its role in complex diseases is poorly understood. We performed cap analysis of gene expression (CAGE) tag sequencing from the left ventricle (LV) of a rat model of hypertension, the spontaneously hypertensive rat (SHR), and a normotensive strain, the Brown Norway (BN) to understand role of alternative promoter usage in complex disease. We identified 26,560 CAGE-defined transcription start sites (TSS) in the rat LV, including 1,970 novel cardiac TSS resulting in new transcripts. We identified 27 genes with alternative promoter usage between SHR and BN which could lead to protein isoforms differing at the amino terminus between two strains. Additionally, we identified 475 promoter switching events where a shift in TSS usage was within 100bp between SHR and BN, altering length of the 5 prime UTR. Genomic variants located in the shifting promoter regions showed significant allelic imbalance in F1 crosses, confirming promoter shift. We found that the insulin receptor gene (Insr) showed a switch in promoter usage between SHR and BN in heart and liver. The Insr promoter shift was significantly associated with insulin levels and blood pressure within a panel of BXH/HXB recombinant inbred (RI) rat strains. This suggests that the hyperinsulinemia due to insulin resistance might lead to hypertension in SHR. Our study provides a preliminary evidence of alternative promoter usage in complex diseases.

Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting

2019 ◽  
Vol 78 (4) ◽  
pp. 529-538 ◽  
Author(s):  
Maarten van der Kroef ◽  
Monica Castellucci ◽  
Michal Mokry ◽  
Marta Cossu ◽  
Marianna Garonzi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Chromatin Immunoprecipitation ◽  
Transcription Start ◽  
Histone Marks ◽  
Transcription Start Sites ◽  
Altered Gene Expression ◽  
Bromodomain Proteins ◽  
Altered Gene

Background and objectiveSystemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes.MethodsChromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFN-responsive gene expression.Results1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFNα induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression.ConclusionSSc monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc.

scholarly journals Alternative promoter usage modulates miRNA-guided translation inhibition of a m6A reader in phosphate starvation

2020 ◽  
Author(s):  
Rodrigo Siqueira Reis ◽  
Jules Deforges ◽  
Joaquín Clúa ◽  
Yves Poirier
Keyword(s):  
Protein Isoforms ◽  
Phosphate Deficiency ◽  
Transcription Start ◽  
Translation Inhibition ◽  
Transcription Start Sites ◽  
Phosphate Availability ◽  
Alternative Transcription ◽  
Promoter Usage ◽  
Alternative Tsss

AbstractAlternative transcription start sites (TSSs) are widespread in eukaryotes. In plants, light, development and tissue regulate selective usage of several TSSs, producing transcripts with distinct 5′UTR as well as shorter protein isoforms with distinct subcellular localization or activity. However, the function of non-coding transcripts generated by alternative TSSs is still largely unknown. We show that phosphate availability regulates numerous alternative TSSs, including a non-coding alternative TSS (ALTECT4) associated with ECT4, encoding a N6-methyladenosine (m6A) reader. We found that ECT4 harbors a cleavage-resistant miR826b target site at its 3’UTR, also present in ALTECT4. In the absence of ALTECT4, miR826b guides translation inhibition of ECT4. Phosphate deficiency triggers specific and robust expression of ALTECT4, counteracting miR826b inhibition of its targets, including ECT4. The role of ALTECT4 as a miR826b antagonist shows that it acts in cis to regulate translation of the m6A reader ECT4, and this function might be shared among other non-coding transcripts generated by alternative TSS.

scholarly journals Cap-proximal nucleotides via differential eIF4E binding and alternative promoter usage mediate translational response to energy stress

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Ana Tamarkin-Ben-Harush ◽  
Jean-Jacques Vasseur ◽  
Françoise Debart ◽  
Igor Ulitsky ◽  
Rivka Dikstein
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Transcription Start Site ◽  
Alternative Promoter ◽  
Start Site ◽  
Glucose Starvation ◽  
Transcription Start ◽  
Dramatic Effect ◽  
Energy Stress ◽  
Promoter Usage

Transcription start-site (TSS) selection and alternative promoter (AP) usage contribute to gene expression complexity but little is known about their impact on translation. Here we performed TSS mapping of the translatome following energy stress. Assessing the contribution of cap-proximal TSS nucleotides, we found dramatic effect on translation only upon stress. As eIF4E levels were reduced, we determined its binding to capped-RNAs with different initiating nucleotides and found the lowest affinity to 5'cytidine in correlation with the translational stress-response. In addition, the number of differentially translated APs was elevated following stress. These include novel glucose starvation-induced downstream transcripts for the translation regulators eIF4A and Pabp, which are also translationally-induced despite general translational inhibition. The resultant eIF4A protein is N-terminally truncated and acts as eIF4A inhibitor. The induced Pabp isoform has shorter 5'UTR removing an auto-inhibitory element. Our findings uncovered several levels of coordination of transcription and translation responses to energy stress.

Cap Analysis of Gene Expression (CAGE): A Quantitative and Genome-Wide Assay of Transcription Start Sites

2020 ◽  
pp. 277-301 ◽  
Author(s):  
Masaki Suimye Morioka ◽  
Hideya Kawaji ◽  
Hiromi Nishiyori-Sueki ◽  
Mitsuyoshi Murata ◽  
Miki Kojima-Ishiyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Genome Wide ◽  
Cap Analysis

scholarly journals CAGEfightR: Cap Analysis of Gene Expression (CAGE) in R/Bioconductor

2018 ◽  
Author(s):  
Malte Thodberg ◽  
Axel Thieffry ◽  
Kristoffer Vitting-Seerup ◽  
Robin Andersson ◽  
Albin Sandelin
Keyword(s):  
Gene Expression ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Link Type ◽  
Shape Statistics ◽  
Downstream Analysis ◽  
Cap Analysis ◽  
Memory Efficient

AbstractWe developed the CAGEfightR R/Biconductor-package for analyzing CAGE data. CAGEfightR allows for fast and memory efficient identification of transcription start sites (TSSs) and predicted enhancers. Downstream analysis, including annotation, quantification, visualization and TSS shape statistics are implemented in easy-to-use functions. The package is freely available at https://bioconductor.org/packages/CAGEfightR

scholarly journals Retinal transcriptome profiling at transcription start sites: a cap analysis of gene expression early after axonal injury

BMC Genomics ◽  
2014 ◽  
Vol 15 (1) ◽  
pp. 982 ◽  
Author(s):  
Masayuki Yasuda ◽  
Yuji Tanaka ◽  
Koji M Nishiguchi ◽  
Morin Ryu ◽  
Satoru Tsuda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Axonal Injury ◽  
Transcriptome Profiling ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Cap Analysis

scholarly journals A step-by-step guide to analyzing CAGE data using R/Bioconductor

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 886 ◽  
Author(s):  
Malte Thodberg ◽  
Albin Sandelin
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Differential Expression Analysis ◽  
Transcription Start ◽  
Single Experiment ◽  
Transcription Start Sites ◽  
Bioconductor Project ◽  
Advanced Analysis ◽  
Cap Analysis

Cap Analysis of Gene Expression (CAGE) is one of the most popular 5'-end sequencing methods. In a single experiment, CAGE can be used to locate and quantify the expression of both Transcription Start Sites (TSSs) and enhancers. This is workflow is a case study on how to use the CAGEfightR package to orchestrate analysis of CAGE data within the Bioconductor project. This workflow starts from BigWig-files and covers both basic CAGE analyses such as identifying, quantifying and annotating TSSs and enhancers, advanced analysis such as finding interacting TSS-enhancer pairs and enhancer clusters, to differential expression analysis and alternative TSS usage. R-code, discussion and references are intertwined to help provide guidelines for future CAGE studies of the same kind.

scholarly journals Altered Enhancer and Promoter Usage Leads to Differential Gene Expression in the Normal and Failed Human Heart

2020 ◽  
Vol 13 (10) ◽  
Author(s):  
Anthony M. Gacita ◽  
Lisa Dellefave-Castillo ◽  
Patrick G.T. Page ◽  
David Y. Barefield ◽  
J. Andrew Wasserstrom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Regulatory Function ◽  
Specific Gene ◽  
Data Set ◽  
Promoter Usage ◽  
Additional Support ◽  
Cap Analysis ◽  
Genetic Contributions

Background: The failing heart is characterized by changes in gene expression. However, the regulatory regions of the genome that drive these gene expression changes have not been well defined in human hearts. Methods: To define genome-wide enhancer and promoter use in heart failure, cap analysis of gene expression sequencing was applied to 3 healthy and 4 failed human hearts to identify promoter and enhancer regions used in left ventricles. Healthy hearts were derived from donors unused for transplantation and failed hearts were obtained as discarded tissue after transplantation. Results: Cap analysis of gene expression sequencing identified a combined potential for ≈23 000 promoters and ≈5000 enhancers active in human left ventricles. Of these, 17 000 promoters and 1800 enhancers had additional support for their regulatory function. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered aminoterminal protein sequences. Enhancer usage between healthy and failed hearts identified a majority of differentially used heart failure enhancers were intronic and primarily localized within the first intron, revealing this position as a common feature associated with tissue-specific gene expression changes in the heart. Conclusions: This data set defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction. Additionally, regulatory changes contributing to heart failure are attractive therapeutic targets for controlling ventricular remodeling and clinical progression.

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