A description of the relationship in healthy longevity and aging-related disease: from gene to protein

AbstractHuman longevity is a complex phenotype influenced by both genetic and environmental factors. It is also known to be associated with various types of age-related diseases, such as Alzheimer’s disease (AD) and cardiovascular disease (CVD). The central dogma of molecular biology demonstrates the conversion of DNA to RNA to the encoded protein. These proteins interact to form complex cell signaling pathways, which perform various biological functions. With prolonged exposure to the environment, the in vivo homeostasis adapts to the changes, and finally, humans adopt the phenotype of longevity or aging-related diseases. In this review, we focus on two different states: longevity and aging-related diseases, including CVD and AD, to discuss the relationship between genetic characteristics, including gene variation, the level of gene expression, regulation of gene expression, the level of protein expression, both genetic and environmental influences and homeostasis based on these phenotypes shown in organisms.

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highroad is induced by retinoids and clears mutant Rhodopsin-1 in Drosophila Retinitis Pigmentosa models

10.1101/204131 ◽

2017 ◽

Author(s):

Huai-Wei Huang ◽

Brian Brown ◽

Jaehoon Chung ◽

Pedro M. Domingos ◽

Hyung Don Ryoo

Keyword(s):

Gene Expression ◽

Genetic Interaction ◽

Regulation Of Gene Expression ◽

Regulate Gene Expression ◽

Age Related ◽

Defective Mutant ◽

Quality Control Mechanism ◽

Santa Maria ◽

Inducible Gene

AbstractThe light detecting protein, Rhodopsin, requires retinoid chromophores for their function. In vertebrates, retinoids also serve as signaling molecules, but whether these molecules similarly regulate gene expression in Drosophila remains unclear. Here, we report the identification of a retinoid-inducible gene in Drosophila, highroad, which is required for photoreceptors to clear folding-defective mutant Rhodopsin-1 proteins. Specifically, we identified highroad through an in vivo RNAi based genetic interaction screen with one such folding defective Rhodopsin-1 mutant, ninaEG69D. CRISPR-Cas9-mediated deletion of highroad results in the stabilization of folding-defective mutant Rhodopsin-1 proteins, and acceleration of the age-related retinal degeneration phenotype of ninaEG69D mutants. Elevated highroad transcript levels are detected ninaEG69D flies, and interestingly, deprivation of retinoids in the fly diet blocks this effect. Consistently, mutations in the retinoid transporter santa maria impairs the induction of highroad in ninaEG69D flies. In cultured S2 cells, highroad expression is induced by retinoic acid treatment. These results indicate that cellular quality control mechanism against misfolded Rhodopsin-1 involves regulation of gene expression by retinoids.

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A joint analysis of longevity and age-related disease variants for gene expression association

10.1101/2021.01.25.428082 ◽

2021 ◽

Author(s):

Lu Zeng ◽

Shouneng Peng ◽

Seungsoo Kim ◽

Jun Zhu ◽

Bin Zhang ◽

...

Keyword(s):

Gene Expression ◽

Genetic Variants ◽

Gene Expression Regulation ◽

Human Longevity ◽

Joint Analysis ◽

Putative Gene ◽

Related Disease ◽

Age Related ◽

Genome Wide

AbstractA large number of genetic variants associated with human longevity have been reported but how they play their functions remains elusive. We performed an integrative analysis on 113 genome-wide significant longevity and 14,529 age-related disease variants in the context of putative gene expression regulation. We found that most of the longevity allele types were different from the genotype of disease alleles when they were localized at the same chromosomal positions. Longevity variants were about eight times more likely to be associated with gene expression than randomly selected variants. The directions of the gene expression association were more likely to be opposite between longevity and disease variants when the association occurred to the same gene. Many longevity variants likely function through down-regulating inflammatory response and up-regulating healthy lipid metabolisms. In conclusion, this work helps to elucidate the potential mechanisms of longevity variants for follow-up studies to discover methods to extend human healthspan.

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Chromatin proteomics to study epigenetics – challenges and opportunities

Molecular & Cellular Proteomics ◽

10.1074/mcp.r120.002208 ◽

2020 ◽

pp. mcp.R120.002208

Author(s):

Guido van Mierlo ◽

Michiel Vermeulen

Keyword(s):

Gene Expression ◽

Mass Spectrometry ◽

Protein Function ◽

Gene Expression Regulation ◽

Affinity Purification ◽

Regulation Of Gene Expression ◽

Regulatory Elements ◽

Expression Regulation ◽

Genomic Locus

Regulation of gene expression is essential for the functioning of all eukaryotic organisms. Understanding gene expression regulation requires determining which proteins interact with regulatory elements in chromatin. Mass spectrometry-based analysis of chromatin has emerged as a powerful tool to identify proteins associated with gene regulation, as it allows studying protein function and protein complex formation in their in vivo chromatin-bound context. Total chromatin isolated from cells can be directly analysed using mass spectrometry or further fractionated into transcriptionally active and inactive chromatin prior to MS-based analysis. Newly formed chromatin that is assembled during DNA replication can also be specifically isolated and analysed. Furthermore, capturing specific chromatin domains facilitates the identification of previously unknown transcription factors interacting with these domains. Finally, in recent years, advances have been made towards identifying proteins that interact with a single genomic locus of interest. In this review, we highlight the power of chromatin proteomics approaches and how these provide complementary alternatives compared to conventional affinity purification methods. Furthermore, we discuss the biochemical challenges that should be addressed to consolidate and expand the role of chromatin proteomics as a key technology in the context of gene expression regulation and epigenetics research in health and disease.

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Flow-dependent regulation of endothelial Tie2 by GATA3 in vivo

Intensive Care Medicine Experimental ◽

10.1186/s40635-021-00402-x ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Temitayo O. Idowu ◽

Valerie Etzrodt ◽

Thorben Pape ◽

Joerg Heineke ◽

Klaus Stahl ◽

...

Keyword(s):

Gene Expression ◽

Regulation Of Gene Expression ◽

Experimental Models ◽

Common Denominator ◽

Dependent Manner ◽

Pulmonary Endothelium ◽

Delivery Platform ◽

Transient Overexpression ◽

Plasmid Delivery

Abstract Background Reduced endothelial Tie2 expression occurs in diverse experimental models of critical illness, and experimental Tie2 suppression is sufficient to increase spontaneous vascular permeability. Looking for a common denominator among different critical illnesses that could drive the same Tie2 suppressive (thereby leak inducing) phenotype, we identified “circulatory shock” as a shared feature and postulated a flow-dependency of Tie2 gene expression in a GATA3 dependent manner. Here, we analyzed if this mechanism of flow-regulation of gene expression exists in vivo in the absence of inflammation. Results To experimentally mimic a shock-like situation, we developed a murine model of clonidine-induced hypotension by targeting a reduced mean arterial pressure (MAP) of approximately 50% over 4 h. We found that hypotension-induced reduction of flow in the absence of confounding disease factors (i.e., inflammation, injury, among others) is sufficient to suppress GATA3 and Tie2 transcription. Conditional endothelial-specific GATA3 knockdown (B6-Gata3tm1-Jfz VE-Cadherin(PAC)-cerERT2) led to baseline Tie2 suppression inducing spontaneous vascular leak. On the contrary, the transient overexpression of GATA3 in the pulmonary endothelium (jet-PEI plasmid delivery platform) was sufficient to increase Tie2 at baseline and completely block its hypotension-induced acute drop. On the functional level, the Tie2 protection by GATA3 overexpression abrogated the development of pulmonary capillary leakage. Conclusions The data suggest that the GATA3–Tie2 signaling pathway might play a pivotal role in controlling vascular barrier function and that it is affected in diverse critical illnesses with shock as a consequence of a flow-regulated gene response. Targeting this novel mechanism might offer therapeutic opportunities to treat vascular leakage of diverse etiologies.

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How (Epi)Genetic Regulation of the LIM-Domain Protein FHL2 Impacts Multifactorial Disease

Cells ◽

10.3390/cells10102611 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2611

Author(s):

Jayron J. Habibe ◽

Maria P. Clemente-Olivo ◽

Carlie J. de Vries

Keyword(s):

Gene Expression ◽

Genetic Variation ◽

Current Knowledge ◽

Genetic Regulation ◽

Regulation Of Gene Expression ◽

Lim Domain ◽

Multifactorial Diseases ◽

Lim Domains ◽

Age Related

Susceptibility to complex pathological conditions such as obesity, type 2 diabetes and cardiovascular disease is highly variable among individuals and arises from specific changes in gene expression in combination with external factors. The regulation of gene expression is determined by genetic variation (SNPs) and epigenetic marks that are influenced by environmental factors. Aging is a major risk factor for many multifactorial diseases and is increasingly associated with changes in DNA methylation, leading to differences in gene expression. Four and a half LIM domains 2 (FHL2) is a key regulator of intracellular signal transduction pathways and the FHL2 gene is consistently found as one of the top hyper-methylated genes upon aging. Remarkably, FHL2 expression increases with methylation. This was demonstrated in relevant metabolic tissues: white adipose tissue, pancreatic β-cells, and skeletal muscle. In this review, we provide an overview of the current knowledge on regulation of FHL2 by genetic variation and epigenetic DNA modification, and the potential consequences for age-related complex multifactorial diseases.

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Cytomegalovirus Replicon-Based Regulation of Gene Expression In Vitro and In Vivo

PLoS Pathogens ◽

10.1371/journal.ppat.1002728 ◽

2012 ◽

Vol 8 (6) ◽

pp. e1002728 ◽

Cited By ~ 7

Author(s):

Hermine Mohr ◽

Christian A. Mohr ◽

Marlon R. Schneider ◽

Laura Scrivano ◽

Barbara Adler ◽

...

Keyword(s):

Gene Expression ◽

Regulation Of Gene Expression

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Comparison of gene expression and activation of transcription factors in organoid-derived monolayer intestinal epithelial cells and organoids

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab136 ◽

2021 ◽

Author(s):

Yu Takahashi ◽

Yu Inoue ◽

Keitaro Kuze ◽

Shintaro Sato ◽

Makoto Shimizu ◽

...

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Gene Expression Regulation ◽

Intestinal Epithelial Cells ◽

Three Dimensional ◽

Culture Conditions ◽

Dependent Manner ◽

Intestinal Epithelial

Abstract Intestinal organoids better represent in vivo intestinal properties than conventionally used established cell lines in vitro. However, they are maintained in three-dimensional culture conditions that may be accompanied by handling complexities. We characterized the properties of human organoid-derived two-dimensionally cultured intestinal epithelial cells (IECs) compared with those of their parental organoids. We found that the expression of several intestinal markers and functional genes were indistinguishable between monolayer IECs and organoids. We further confirmed that their specific ligands equally activate intestinal ligand-activated transcriptional regulators in a dose-dependent manner. The results suggest that culture conditions do not significantly influence the fundamental properties of monolayer IECs originating from organoids, at least from the perspective of gene expression regulation. This will enable their use as novel biological tools to investigate the physiological functions of the human intestine.

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GEREDB: Gene expression regulation database curated by mining abstracts from literature

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720019500240 ◽

2019 ◽

Vol 17 (04) ◽

pp. 1950024 ◽

Cited By ~ 2

Author(s):

Tinghua Huang ◽

Xiali Huang ◽

Bomei Shi ◽

Min Yao

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Gene Expression Regulation ◽

Biological Database ◽

Biological Processes ◽

Expression Data ◽

Biological Responses ◽

Human Genes ◽

The Relationship ◽

Made In

Understanding how genes are expressed and regulated in different biological processes are fundamental and challenging issues. Considerable progress has been made in studying the relationship between the expression and regulation of human genes. However, it is difficult to use these resources productively to analyze gene expression data. GEREDB ( www.thua45.cn/geredb ) has been developed to facilitate analyses that will provide insights into the regulation of genes that govern specific biological responses. GEREDB is a publicly available, manually curated biological database that stores the data regarding relationships between expression and regulation of human genes. To date, more than 39,000 Links have been contextually annotated by reviewing more than 53,000 abstracts. GEREDB can be searched using the official NCBI gene symbol as a query, and it can be downloaded along with the GEREA software package. GEREDB has the ability to analyze user-supplied gene expression data in a causal analysis oriented manner using the GEREA bioinformatics tool.

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RNA Modifications in the Central Nervous System

The Oxford Handbook of Neuronal Protein Synthesis ◽

10.1093/oxfordhb/9780190686307.013.23 ◽

2020 ◽

Cited By ~ 1

Author(s):

Dan Ohtan Wang

Keyword(s):

Gene Expression ◽

Cell Function ◽

Gene Expression Regulation ◽

Spinal Injury ◽

Regulation Of Gene Expression ◽

Modified Nucleosides ◽

Rna Modifications ◽

The Central Nervous System ◽

Post Transcriptional Regulation ◽

The Brain

Epitranscriptomics, a recently emerged field to investigate post-transcriptional regulation of gene expression through enzyme-mediated RNA modifications, is rapidly evolving and integrating with neuroscience. Using a rich repertoire of modified nucleosides and strategically positioning them to the functionally important and evolutionarily conserved regions of the RNA, epitranscriptomics dictates RNA-mediated cell function. The new field is quickly changing our view of the genetic geography in the brain during development and plasticity, impacting major functions from cortical neurogenesis, circadian rhythm, learning and memory, to reward, addiction, stress, stroke, and spinal injury, etc. Thus understanding the molecular components and operational rules of this pathway is becoming a key for us to decipher the genetic code for brain development, function, and disease. What RNA modifications are expressed in the brain? What RNAs carry them and rely on them for function? Are they dynamically regulated? How are they regulated and how do they contribute to gene expression regulation and brain function? This chapter summarizes recent advances that are beginning to answer these questions.

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MicroRNAs in mouse models of lymphoid malignancies

Journal of Nucleic Acids Investigation ◽

10.4081/jnai.2010.1727 ◽

2010 ◽

Vol 1 (1) ◽

pp. 8 ◽

Cited By ~ 5

Author(s):

Nicola A. O. Zanesi ◽

Yuri Pekarsky ◽

Francesco Trapasso ◽

George Calin ◽

Carlo M. Croce

Keyword(s):

Gene Expression ◽

Mouse Models ◽

Gene Expression Regulation ◽

Human Leukemia ◽

Down Regulation ◽

Over Expression ◽

Lymphoid Malignancies ◽

Knockout Animals ◽

Mouse Modeling

The discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation that affects many normal and pathologic biological systems. Among the malignancies affected by the dysregulation of miRNAs there are cancers of lymphoid origin, in which miRNAs are thought to have tumor suppressive or tumor promoting activities, depending on the nature of their specific targets. In the last 4-5 years, the experimental field that provided the deepest insights into the in vivo biology of miRNAs is that of mouse modeling in which transgenic and knockout animals mimic, respectively, over-expression or down-regulation of specific miRNAs involved in human leukemia/lymphoma. This review discusses recent advances in our understanding of lymphoid malignancies based on the natural and engineered mouse models of three different miRNAs, miR-15a/16-1 cluster, miR-155, and miR-17-92 cluster.

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