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.

scholarly journals Enhancer and promoter usage in the normal and failed human heart

2020 ◽  
Author(s):  
Anthony M. Gacita ◽  
Lisa Dellefave-Castillo ◽  
Patrick G. T. Page ◽  
David Y. Barefield ◽  
J. Andrew Waserstrom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Specific Gene ◽  
Amino Terminal ◽  
Short Rnas ◽  
First Intron ◽  
Promoter Usage ◽  
Cap Analysis ◽  
Genetic Contributions ◽  
Regulatory Landscape

ABSTRACTThe failed heart is characterized by re-expression of a fetal gene program, which contributes to adaptation and maladaptation in heart failure. To define genomewide enhancer and promoter use in heart failure, Cap Analysis of Gene Expression (CAGE-seq) was applied to healthy and failed human left ventricles to define short RNAs associated with both promoters and enhancers. Integration of CAGE-seq data with RNA sequencing identified a combined ∼17,000 promoters and ∼1,500 enhancers active in healthy and failed human left ventricles. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered amino-terminal protein sequences. Comparing enhancer usage between healthy and failed hearts revealed a majority of differentially utilized heart failure enhancers were intronic and primarily localized within the first intron, identifying this position as a common feature associated with tissue-specific gene expression changes in the heart. This dataset defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction.

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.

scholarly journals Aspergillus nidulans wetA activates spore-specific gene expression.

1991 ◽  
Vol 11 (1) ◽  
pp. 55-62 ◽  
Author(s):  
M A Marshall ◽  
W E Timberlake
Keyword(s):  
Gene Expression ◽  
Cell Wall ◽  
Aspergillus Nidulans ◽  
Gene Activation ◽  
Regulatory Function ◽  
Specific Gene ◽  
Coding Region ◽  
Vegetative Cells ◽  
Mutant Strains ◽  
Late Stages

The Aspergillus nidulans wetA gene is required for synthesis of cell wall layers that make asexual spores (conidia) impermeable. In wetA mutant strains, conidia take up water and autolyze rather than undergoing the final stages of maturation. wetA is activated during conidiogenesis by sequential expression of the brlA and abaA regulatory genes. To determine whether wetA regulates expression of other sporulation-specific genes, its coding region was fused to a nutritionally regulated promoter that permits gene activation in vegetative cells (hyphae) under conditions that suppress conidiation. Expression of wetA in hyphae inhibited growth and caused excessive branching. It did not lead to activation of brlA or abaA but did cause accumulation of transcripts from genes that are normally expressed specifically during the late stages of conidiation and whose mRNAs are stored in mature spores. Thus, wetA directly or indirectly regulates expression of some spore-specific genes. At least one gene (wA), whose mRNA does not occur in spores but rather accumulates in the sporogenous phialide cells, was activated by wetA, suggesting that wetA may have a regulatory function in these cells as well as in spores. We propose that wetA is responsible for activating a set of genes whose products make up the final two conidial wall layers or direct their assembly and through this activity is responsible for acquisition of spore dormancy.

BIOMARKER DISCOVERY AND VISUALIZATION IN GENE EXPRESSION DATA WITH EFFICIENT GENERALIZED MATRIX APPROXIMATIONS

2007 ◽  
Vol 05 (02a) ◽  
pp. 251-279 ◽  
Author(s):  
WENYUAN LI ◽  
YANXIONG PENG ◽  
HUNG-CHUNG HUANG ◽  
YING LIU
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Biomarker Discovery ◽  
Attribute Selection ◽  
Specific Gene ◽  
Expression Data ◽  
Selection Methods ◽  
Data Set ◽  
Generalized Matrix ◽  
Matrix Approximations

In most real-world gene expression data sets, there are often multiple sample classes with ordinals, which are categorized into the normal or diseased type. The traditional feature or attribute selection methods consider multiple classes equally without paying attention to the up/down regulation across the normal and diseased types of classes, while the specific gene selection methods particularly consider the differential expressions across the normal and diseased, but ignore the existence of multiple classes. In this paper, to improve the biomarker discovery, we propose to make the best use of these two aspects: the differential expressions (that can be viewed as the domain knowledge of gene expression data) and the multiple classes (that can be viewed as a kind of data set characteristic). Therefore, we simultaneously take into account these two aspects by employing the 1-rank generalized matrix approximations (GMA). Our results show that GMA cannot only improve the accuracy of classifying the samples, but also provide a visualization method to effectively analyze the gene expression data on both genes and samples. Based on the mechanism of matrix approximation, we further propose an algorithm, CBiomarker, to discover compact biomarker by reducing the redundancy.

Abstract 115: Cell-type-specific Gene Expression And Transcriptional Networks Reveal Adamts2 As A Powerful Regulator Of Cardiac Homeostasis During Heart Failure

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Caitlin Lahue ◽  
Douglas Chapski ◽  
Manuel Rosa Garrido ◽  
Shuxun Ren ◽  
Thomas M Vondriska ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Careful Examination ◽  
Transcriptional Networks ◽  
Tunel Staining ◽  
Specific Gene ◽  
Paracrine Signaling ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Cell Type Specific

Background: Heart failure (HF) is a highly heterogeneous disorder characterized by the interactions of multiple genetic and environmental factors as well as the interaction of different cell types in the heart. Although reductionistic approaches have successfully identified many genes involved in HF, heritability studies suggest that many genes have resisted discovery through these approaches. By utilizing cell-type-specific gene expression paired with transcriptomic data from a large cohort of mice, we sought to identify important drivers of HF using a systems genetics approach. Methods and Results: Mice from 93 unique inbred lines of the Hybrid Mouse Diversity Panel were given 30 ug/g/day of isoproterenol for three weeks via osmotic minipump to induce heart failure. Transcriptomes were generated from these mice and the weighted Maximal Information Component Analysis (wMICA) algorithm was applied to generate transcriptomic gene networks. Cardiomyocytes and Fibroblasts were isolated from both control and isoproterenol-treated adult C57BL/6J hearts using a Langendorff apparatus (n=3 per sex/treatment) and transcriptomes were generated. Significantly differentially expressed genes were identified using DESEQ2 and used to query the wMICA-derived network, identifying the gene Adamts2 as a potential regulator of cardiac hypertrophy. Follow-up in vitro and in vivo work has demonstrated that Adamts2 knockdown significantly blunts the hypertrophic effect of isoproterenol on cardiomyocytes while simultaneously reducing fibroblast proliferation and increasing apoptosis as measured by TUNEL staining. Careful examination of the gene network reveals evidence of paracrine signaling between cardiomyocytes and fibroblasts and suggests a key trans-cell-type role of Adamts2 in the regulation of HF after catecholamine stimulation. Conclusion: Co-expression network algorithms combined with cell-type-specific transcriptomics identified Adamts2 as a driver of HF. Adamts2 plays an important role via paracrine signaling in the proliferative response of fibroblasts and the hypertrophic response of cardiomyocytes to catecholamines. Further mechanistic analysis of Adamts2 will further reveal its role in the progression of heart failure.

scholarly journals Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation.

1997 ◽  
Vol 17 (12) ◽  
pp. 6815-6821 ◽  
Author(s):  
R W Deed ◽  
E Hara ◽  
G T Atherton ◽  
G Peters ◽  
J D Norton
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Complex Formation ◽  
S Phase ◽  
Regulatory Function ◽  
Specific Gene ◽  
Wild Type ◽  
E Box ◽  
Phase Entry

The functions of basic helix-loop-helix (bHLH) transcription factors in activating differentiation-linked gene expression and in inducing G1 cell cycle arrest are negatively regulated by members of the Id family of HLH proteins. These bHLH antagonists are induced during a mitogenic signalling response, and they function by sequestering their bHLH targets in inactive heterodimers that are unable to bind to specific gene regulatory (E box) sequences. Recently, cyclin E-Cdk2- and cyclin A-Cdk2-dependent phosphorylation of a single conserved serine residue (Ser5) in Id2 has been shown to occur during late G1-to-S phase transition of the cell cycle, and this neutralizes the function of Id2 in abrogating E-box-dependent bHLH homo- or heterodimer complex formation in vitro (E. Hara, M. Hall, and G. Peters, EMBO J. 16:332-342, 1997). We now show that an analogous cell-cycle-regulated phosphorylation of Id3 alters the specificity of Id3 for abrogating both E-box-dependent bHLH homo- or heterodimer complex formation in vitro and E-box-dependent reporter gene function in vivo. Furthermore, compared with wild-type Id3, an Id3 Asp5 mutant (mimicking phosphorylation) is unable to promote cell cycle S phase entry in transfected fibroblasts, whereas an Id3 Ala5 mutant (ablating phosphorylation) displays an activity significantly greater than that of wild-type Id3 protein. Cdk2-dependent phosphorylation therefore provides a switch during late G1-to-S phase that both nullifies an early G1 cell cycle regulatory function of Id3 and modulates its target bHLH specificity. These data also demonstrate that the ability of Id3 to promote cell cycle S phase entry is not simply a function of its ability to modulate bHLH heterodimer-dependent gene expression and establish a biologically important mechanism through which Cdk2 and Id-bHLH functions are integrated in the coordination of cell proliferation and differentiation.

Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure

2005 ◽  
Vol 21 (3) ◽  
pp. 314-323 ◽  
Author(s):  
Henk P. J. Buermans ◽  
Everaldo M. Redout ◽  
Anja E. Schiel ◽  
René J. P. Musters ◽  
Marian Zuidwijk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Contractile Function ◽  
Pyrrolizidine Alkaloid ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pressure Overload ◽  
High Dose ◽  
Specific Expression

Myocardial right ventricular (RV) hypertrophy due to pulmonary hypertension is aimed at normalizing ventricular wall stress. Depending on the degree of pressure overload, RV hypertrophy may progress to a state of impaired contractile function and heart failure, but this cannot be discerned during the early stages of ventricular remodeling. We tested whether critical differences in gene expression profiles exist between ventricles before the ultimate development of either a compensated or decompensated hypertrophic phenotype. Both phenotypes were selectively induced in Wistar rats by a single subcutaneous injection of either a low or a high dose of the pyrrolizidine alkaloid monocrotaline (MCT). Spotted oligonucleotide microarrays were used to investigate pressure-dependent cardiac gene expression profiles at 2 wk after the MCT injections, between control rats and rats that would ultimately develop either compensated or decompensated hypertrophy. Clustering of significantly regulated genes revealed specific expression profiles for each group, although the degree of hypertrophy was still similar in both. The ventricles destined to progress to failure showed activation of pro-apoptotic pathways, particularly related to mitochondria, whereas the group developing compensated hypertrophy showed blocked pro-death effector signaling via p38-MAPK, through upregulation of MAPK phosphatase-1. In summary, we show that, already at an early time point, pivotal differences in gene expression exist between ventricles that will ultimately develop either a compensated or a decompensated phenotype, depending on the degree of pressure overload. These data reveal genes that may provide markers for the early prediction of clinical outcome as well as potential targets for early intervention.

scholarly journals A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure

2021 ◽  
Vol 14 (676) ◽  
pp. eabb5968
Author(s):  
Ryan C. Coleman ◽  
Akito Eguchi ◽  
Melissa Lieu ◽  
Rajika Roy ◽  
Eric W. Barr ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
G Protein ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Nuclear Accumulation ◽  
Nuclear Targeting ◽  
Amino Terminal

Aberrant changes in gene expression underlie the pathogenesis and progression of pressure-overload heart failure, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. Signaling through the G protein Gq triggers maladaptation and heart failure, in part through the activation of G protein–coupled receptor kinase 5 (GRK5). Hypertrophic stimuli induce the accumulation of GRK5 in the nuclei of cardiomyocytes, where it regulates pathological gene expression through multiple transcription factors including NFAT. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that binds to calmodulin (CaM). Here, we sought to prevent GRK5-mediated pathology in pressure-overload maladaptation and heart failure by expressing in cardiomyocytes a peptide encoding the GRK5 NT (GRK5nt) that encompasses the CaM binding domain. In cultured cardiomyocytes, GRK5nt expression abrogated Gq-coupled receptor–mediated hypertrophy, including attenuation of pathological gene expression and the transcriptional activity of NFAT and NF-κB. We confirmed that GRK5nt bound to and blocked Ca2+-CaM from associating with endogenous GRK5, thereby preventing GRK5 nuclear accumulation after pressure overload. We generated mice that expressed GRKnt in a cardiac-specific fashion (TgGRK5nt mice), which exhibited reduced cardiac hypertrophy, ventricular dysfunction, pulmonary congestion, and cardiac fibrosis after chronic transverse aortic constriction. Together, our data support a role for GRK5nt as an inhibitor of pathological GRK5 signaling that prevents heart failure.

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