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

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

Immunity & Ageing ◽

10.1186/s12979-021-00241-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Xiaolin Ni ◽

Zhaoping Wang ◽

Danni Gao ◽

Huiping Yuan ◽

Liang Sun ◽

...

Keyword(s):

Gene Expression ◽

Prolonged Exposure ◽

Gene Expression Regulation ◽

Regulation Of Gene Expression ◽

Human Longevity ◽

Form Complex ◽

Genetic Characteristics ◽

Age Related ◽

The Relationship

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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Drosophila fabp is a retinoid-inducible gene required for Rhodopsin-1 homeostasis and photoreceptor survival

10.1101/2021.04.16.440122 ◽

2021 ◽

Author(s):

Hyung Don Ryoo ◽

Huai-Wei Huang

Keyword(s):

Gene Expression ◽

Specific Gene ◽

Fatty Acid Binding ◽

Regulate Gene Expression ◽

Protein Levels ◽

Expression Of Genes ◽

Light Loss ◽

Regulate Gene ◽

Inducible Gene

Retinoids act as chromophore co-factors for light-detecting rhodopsin proteins. In vertebrates, retinoids also actively regulate gene expression. Whether retinoids regulate gene expression in Drosophila for a specific biological function remains unclear. Here, we report that Drosophila fatty acid binding protein ( fabp ) is a retinoid-inducible gene required for Rhodopsin-1 (Rh1) protein homeostasis and photoreceptor survival. Specifically, we performed a photoreceptor-specific gene expression profiling study in flies bearing a misfolding-prone Rhodopsin-1 (Rh1) mutant, ninaE G69D , which serves as a Drosophila model for Retinitis Pigmentosa. ninaE G69D photoreceptors showed increased expression of genes that control Rh1 protein levels, along with a poorly characterized gene, fabp . We found that in vivo fabp expression was reduced when the retinoids were deprived through independent methods. Conversely, fabp mRNA was induced when we challenged cultured Drosophila cells with retinoic acid. In flies reared under light, loss of fabp caused an accumulation of Rh1 proteins in cytoplasmic vesicles. fabp mutants exhibited light-dependent retinal degeneration, a phenotype also found in other mutants that block light-activated Rh1 degradation. These observations indicate that a retinoid-inducible gene expression program regulates fabp that is required forRh1 proteostasis and photoreceptor survival.

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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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Enhancers Predominantly Regulate Gene Expression in vivo Via Transcription Initiation

SSRN Electronic Journal ◽

10.2139/ssrn.3508885 ◽

2019 ◽

Cited By ~ 1

Author(s):

Martin Stephen Charles Larke ◽

Takayuki Nojima ◽

Jelena Telenius ◽

Jacqueline A. Sharpe ◽

Jacqueline A. Sloane-Stanley ◽

...

Keyword(s):

Gene Expression ◽

Transcription Initiation ◽

Regulate Gene Expression ◽

Regulate Gene

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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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Polyamines regulate gene expression by stimulating translation of histone acetyltransferase mRNAs

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013833 ◽

2020 ◽

Vol 295 (26) ◽

pp. 8736-8745 ◽

Cited By ~ 1

Author(s):

Akihiko Sakamoto ◽

Yusuke Terui ◽

Takeshi Uemura ◽

Kazuei Igarashi ◽

Keiko Kashiwagi

Keyword(s):

Gene Expression ◽

Regulation Of Gene Expression ◽

Histone Acetyltransferases ◽

Regulate Gene Expression ◽

Double Stranded Rna ◽

Protein Levels ◽

Lysine Residues ◽

Regulate Gene ◽

Stimulation Of

Polyamines regulate gene expression in Escherichia coli by translationally stimulating mRNAs encoding global transcription factors. In this study, we focused on histone acetylation, one of the mechanisms of epigenetic regulation of gene expression, to attempt to clarify the role of polyamines in the regulation of gene expression in eukaryotes. We found that activities of histone acetyltransferases in both the nucleus and cytoplasm decreased significantly in polyamine-reduced mouse mammary carcinoma FM3A cells. Although protein levels of histones H3 and H4 did not change in control and polyamine-reduced cells, acetylation of histones H3 and H4 was greatly decreased in the polyamine-reduced cells. Next, we used control and polyamine-reduced cells to identify histone acetyltransferases whose synthesis is stimulated by polyamines. We found that polyamines stimulate the translation of histone acetyltransferases GCN5 and HAT1. Accordingly, GCN5- and HAT1-catalyzed acetylation of specific lysine residues on histones H3 and H4 was stimulated by polyamines. Consistent with these findings, transcription of genes required for cell proliferation was enhanced by polyamines. These results indicate that polyamines regulate gene expression by enhancing the expression of the histone acetyltransferases GCN5 and HAT1 at the level of translation. Mechanistically, polyamines enhanced the interaction of microRNA-7648-5p (miR-7648-5p) with the 5′-UTR of GCN5 mRNA, resulting in stimulation of translation due to the destabilization of the double-stranded RNA (dsRNA) between the 5′-UTR and the ORF of GCN5 mRNA. Because HAT1 mRNA has a short 5′-UTR, polyamines may enhance initiation complex formation directly on this mRNA.

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Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1517140113 ◽

2016 ◽

Vol 113 (13) ◽

pp. E1835-E1843 ◽

Cited By ~ 8

Author(s):

Mina Fazlollahi ◽

Ivor Muroff ◽

Eunjee Lee ◽

Helen C. Causton ◽

Harmen J. Bussemaker

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Target Genes ◽

Regulation Of Gene Expression ◽

Nonsynonymous Mutation ◽

Gene Regulatory ◽

Genetic Modulators

Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae. We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.

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