Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

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PHACTR1, a pro-atherosclerotic mechanosensitive PPARgamma corepressor in endothelial cells

European Heart Journal ◽

10.1093/ehjci/ehaa946.3763 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

D Jiang ◽

H Liu ◽

G Zhu ◽

X Li ◽

L Fan ◽

...

Keyword(s):

Endothelial Cells ◽

Molecular Mechanisms ◽

Association Studies ◽

Inhibitory Effect ◽

Funding Source ◽

Genome Wide Association Studies ◽

Aortic Sinus ◽

National Budget ◽

Plaque Area

Abstract Background Numerous genome-wide association studies revealed that SNPs at phosphatase and actin regulator 1 (PHACTR1) locus are strongly correlated with coronary artery disease (CAD). However, the mechanism linking these variants to CAD remains uncertain. Purpose We studied the biological functions and molecular mechanisms of PHACTR1 in atherosclerosis. Methods and results Analysis of GTEx database showed that CAD-related SNPs in PHACTR1 are cis-eQTLs for PHACTR1 in arteries. Therefore, we generated Phactr1 knockout mice and crossed them with apolipoprotein E-deficient (ApoE−/−) mice to induce atherosclerosis by high-fat/high-cholesterol (HF-HC) diet. Phactr1 deficiency significantly inhibited atherosclerosis with decreased inflammatory cell infiltration. Western blot showed that PHACTR1 was restricted to endothelial cells (ECs) in mice. Mechanistically, RNAseq of aortic ECs revealed that the major molecular function of PHACTR1 was transcriptional regulation. PPARγ/RXRα was the top transcription factor, and PPARγ target gene expression substantially increased in Phactr1−/− mice. Moreover, we generated endothelial cell specific Phactr1−/−, ApoE−/− mice and found decreased atherosclerotic plaque area in aortic sinus. In vitro, PHACTR1 associated with PPARγ and inhibited PPARγ transcriptional activity. The inhibitory effect of PHACTR1 on PPARγ required its shuttling from cytosol to nucleus triggered by disturbed flow, a well-established pro-atherosclerotic stimulus. Conclusion Our results identified PHACTR1 as a mechanosensitive corepressor of PPARγ in ECs to promote atherosclerosis. Endothelial PHACTR1 is a potential therapeutic target for atherosclerosis treatment. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China (NSFC), China Postdoctoral Science Foundation (CPSF)

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The Transcription Factor MAFF Regulates an Atherosclerosis Relevant Network Connecting Inflammation and Cholesterol Metabolism

Circulation ◽

10.1161/circulationaha.120.050186 ◽

2021 ◽

Author(s):

Moritz von Scheidt ◽

Yuqi Zhao ◽

Thomas Q. de Aguiar Vallim ◽

Nam Che ◽

Michael Wierer ◽

...

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Prediction Models ◽

Cholesterol Metabolism ◽

Association Studies ◽

Experimental Studies ◽

Genome Wide Association Studies ◽

Inflammatory Conditions

Background: Coronary artery disease (CAD) is a multifactorial condition with both genetic and exogenous causes. The contribution of tissue specific functional networks to the development of atherosclerosis remains largely unclear. The aim of this study was to identify and characterise central regulators and networks leading to atherosclerosis. Methods: Based on several hundred genes known to affect atherosclerosis risk in mouse (as demonstrated in knock-out models) and human (as shown by genome-wide association studies (GWAS)) liver gene regulatory networks were modeled. The hierarchical order and regulatory directions of genes within the network were based on Bayesian prediction models as well as experimental studies including chromatin immunoprecipitation DNA-Sequencing (ChIP-Seq), ChIP mass spectrometry (ChIP-MS), overexpression, siRNA knockdown in mouse and human liver cells, and knockout mouse experiments. Bioinformatics and correlation analyses were used to clarify associations between central genes and CAD phenotypes in both human and mouse. Results: The transcription factor MAFF interacted as a key driver of a liver network with three human genes at CAD GWAS loci and eleven atherosclerotic murine genes. Most importantly, expression levels of the low-density lipoprotein receptor ( LDLR ) gene correlated with MAFF in 600 CAD patients undergoing bypass surgery (STARNET) and a hybrid mouse diversity panel involving 105 different inbred mouse strains. Molecular mechanisms of MAFF were tested under non-inflammatory conditions showing a positive correlation between MAFF and LDLR in vitro and in vivo . Interestingly, after LPS stimulation (inflammatory conditions) an inverse correlation between MAFF and LDLR in vitro and in vivo was observed. ChIP-MS revealed that the human CAD GWAS candidate BACH1 assists MAFF in the presence of LPS stimulation with respective heterodimers binding at the MAF recognition element (MARE) of the LDLR promoter to transcriptionally downregulate LDLR expression. Conclusions: The transcription factor MAFF was identified as a novel central regulator of an atherosclerosis/CAD relevant liver network. MAFF triggered context specific expression of LDLR and other genes known to affect CAD risk. Our results suggest that MAFF is a missing link between inflammation, lipid and lipoprotein metabolism and a possible treatment target.

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Abstract MP150: Inositol 1,4,5-trisphosphate Receptors Selectively Regulate Detrimental Cardiac Fibrosis by Modulating ER-phagy

Circulation Research ◽

10.1161/res.127.suppl_1.mp150 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Gaetano Santulli ◽

Marco Morelli ◽

Xujun Wang ◽

John Ferrante ◽

Jessica Gambardella

Keyword(s):

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Ex Vivo ◽

Myocardial Dysfunction ◽

Association Studies ◽

Experimental Studies ◽

Genome Wide Association Studies ◽

Inositol 1,4,5 Trisphosphate

Background: Therapeutic strategies that specifically target excessive post-ischemic cardiac fibrosis are lacking but desperately needed; thus, it is critical to understand the molecular mechanisms underlying these processes. Genome-wide association studies have revealed an association between inositol 1,4,5-trisphosphate receptors (IP3Rs) and ischemic heart disease. However, experimental studies examining the exact role of IP3Rs in post-ischemic cardiac fibrosis are missing. Aim: We hypothesize that IP3Rs play a key role in the regulation of cardiac myofibroblasts (myoFBs) in healing the infarcted heart after myocardial infarction (MI). Methods: We performed an integrated set of in vivo, ex vivo , and in vitro experiments aiming at identifying the functional role of cardiac myoFB IP3Rs in post-ischemic cardiac remodeling. We generated cardiac myo-FB-specific Triple IP3R knock-out (IP3R TKO ) mice ( Cre/lox recombination technique; Promoter: Periostin ), allowing us to overcome the difficulties encountered following the KO or KD of a single (of the three existent) IP3Rs, a strategy that has been shown to induce compensatory upregulation of the other isoforms. Results: After MI, IP3Rs are significantly upregulated in myoFBs of the remote regions but not in the scar area. IP3R TKO mice display a significantly reduced interstitial cardiac fibrosis and a markedly attenuated myocardial dysfunction following MI compared with control IP3R flox or Periostin Cre littermates. Moreover, FBs lacking IP3Rs exhibit significantly reduced migratory and secretory capacities, a finding confirmed both in murine and human FBs. Mechanistically, we show that IP3Rs modulate endoplasmic reticulum autophagy (ER-phagy) in primary isolated myoFBs following ischemic injury. Conclusions: Taken together, our findings indicate for the first time that IP3Rs are essential for the regulation of post-ischemic cardiac fibrosis.

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RETRACTION: Illuminating the dark road from schizophrenia genetic associations to disease mechanisms

National Science Review ◽

10.1093/nsr/nww065 ◽

2016 ◽

Vol 4 (2) ◽

pp. 240-251 ◽

Cited By ~ 2

Author(s):

Ming Li ◽

Daniel R Weinberger

Keyword(s):

Large Scale ◽

Molecular Mechanisms ◽

Association Studies ◽

Human Populations ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Molecular Approaches ◽

Disease Biology

Abstract Recent large-scale genome-wide association studies (GWAS) have enabled the discovery of common genetic variations contributing to risk architectures of schizophrenia in human populations; however, the majority of GWAS-identified variants are located in large genomic regions spanning multiple genes, and recognizing the precise targets and mechanisms of these clinical associations is now the major challenge. Here, we review recent progress in schizophrenia genetics, functional genomics and related neuroscience research, and propose a functional pipeline to translate schizophrenia GWAS risk loci into disease biology and information for drug discovery. The pipeline includes identification of underlying molecular mechanisms using transcriptomic data in human brain, prioritization of putative functional causative variants by the integration of genetic epidemiological and bioinformatics methods as well as molecular approaches, and in vitro and in vivo experimental characterizations of the identified targeted species and causative variants to dissect the relevant disease biology. These approaches will accelerate progress from schizophrenia genetic studies to biological mechanisms and ultimately guide the development of prognostic, preventive and therapeutic measures.

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Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model

Scientific Reports ◽

10.1038/s41598-021-81550-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gregory R. Keele ◽

Jeremy W. Prokop ◽

Hong He ◽

Katie Holl ◽

John Littrell ◽

...

Keyword(s):

Complex Traits ◽

Genetic Model ◽

Association Studies ◽

Model Systems ◽

Linear Mixed Effect Model ◽

Genome Wide Association Studies ◽

Tubulointerstitial Injury ◽

Heritable Variation ◽

Mixed Effect

AbstractChronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.

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Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa289 ◽

2020 ◽

Author(s):

Niccolo’ Tesi ◽

Sven J van der Lee ◽

Marc Hulsman ◽

Iris E Jansen ◽

Najada Stringa ◽

...

Keyword(s):

Older Adults ◽

Cellular Response ◽

Molecular Mechanisms ◽

Association Studies ◽

Risk Scores ◽

Human Longevity ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

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The migraine–stroke connection: A genetic perspective

Cephalalgia ◽

10.1177/0333102415621055 ◽

2015 ◽

Vol 36 (7) ◽

pp. 658-668 ◽

Cited By ~ 12

Author(s):

Rainer Malik ◽

Bendik Winsvold ◽

Eva Auffenberg ◽

Martin Dichgans ◽

Tobias Freilinger

Keyword(s):

Ischemic Stroke ◽

Vascular Disease ◽

Molecular Mechanisms ◽

Association Studies ◽

Familial Hemiplegic Migraine ◽

Artery Dissection ◽

Cervical Artery Dissection ◽

Data Sets ◽

Genome Wide Association Studies ◽

Disease Manifestation

Background A complex relationship between migraine and vascular disease has long been recognized. The pathophysiological basis underlying this correlation is incompletely understood. Aim The aim of this review is to focus on the migraine–vascular disorders connection from a genetic perspective, illustrating potentially shared (molecular) mechanisms. Results We first summarize the clinical presentation and genetic basis of CADASIL and other monogenic vascular syndromes with migraine as a prominent disease manifestation. Based on data from transgenic mouse models for familial hemiplegic migraine, we then discuss cortical spreading depression as a potential mechanistic link between migraine and ischemic stroke. Finally, we review data from genome-wide association studies, with a focus on overlapping findings with cervical artery dissection, ischemic stroke in general and cardiovascular disease. Conclusion A wealth of data supports a genetic link between migraine and vascular disease. Based on growing high-throughput data-sets, new genotyping techniques and in-depth phenotyping, further insights are expected for the future.

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Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques

Frontiers in Endocrinology ◽

10.3389/fendo.2021.731217 ◽

2021 ◽

Vol 12 ◽

Author(s):

Martina Rauner ◽

Ines Foessl ◽

Melissa M. Formosa ◽

Erika Kague ◽

Vid Prijatelj ◽

...

Keyword(s):

Resource Sharing ◽

Complex Traits ◽

Cellular Localization ◽

Target Genes ◽

Mission Statement ◽

Association Studies ◽

Repetitive Sequences ◽

Genome Wide Association Studies ◽

Causal Genes

The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits (“endophenotypes”), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.

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Identification of Novel Genome-Wide Associations for Oral Inflammatory Traits

10.21203/rs.3.rs-104530/v1 ◽

2020 ◽

Author(s):

Yanjiao Jin ◽

Jie Yang ◽

Shuyue Zhang ◽

Jin Li ◽

Songlin Wang

Keyword(s):

Candidate Genes ◽

Immune Regulation ◽

Functional Annotation ◽

Inflammatory Diseases ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Protein Protein Interaction ◽

Genome Wide ◽

Causal Variants

Abstract Background: Oral diseases impact the majority of the world’s population. The following traits are common in oral inflammatory diseases: mouth ulcers, painful gums, bleeding gums, loose teeth, and toothache. Despite the prevalence of genome-wide association studies, the associations between these traits and common genomic variants, and whether pleiotropic loci are shared by some of these traits remain poorly understood. Methods: In this work, we conducted multi-trait joint analyses based on the summary statistics of genome-wide association studies of these five oral inflammatory traits from the UK Biobank, each of which is comprised of over 10,000 cases and over 300,000 controls. We estimated the genetic correlations between the five traits. We conducted fine-mapping and functional annotation based on multi-omics data to better understand the biological functions of the potential causal variants at each locus. To identify the pathways in which the candidate genes were mainly involved, we applied gene-set enrichment analysis, and further performed protein-protein interaction (PPI) analyses.Results: We identified 39 association signals that surpassed genome-wide significance, including three that were shared between two or more oral inflammatory traits, consistent with a strong correlation. Among these genome-wide significant loci, two were novel for both painful gums and toothache. We performed fine-mapping and identified causal variants at each novel locus. Further functional annotation based on multi-omics data suggested IL10 and IL12A/TRIM59 as potential candidate genes at the novel pleiotropic loci, respectively. Subsequent analyses of pathway enrichment and protein-protein interaction networks suggested the involvement of candidate genes at genome-wide significant loci in immune regulation.Conclusions: Our results highlighted the importance of immune regulation in the pathogenesis of oral inflammatory diseases. Some common immune-related pleiotropic loci or genetic variants are shared by multiple oral inflammatory traits. These findings will be beneficial for risk prediction, prevention, and therapy of oral inflammatory diseases.

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Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

Nature Communications ◽

10.1038/s41467-021-26347-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ivy Aneas ◽

Donna C. Decker ◽

Chanie L. Howard ◽

Débora R. Sobreira ◽

Noboru J. Sakabe ◽

...

Keyword(s):

Association Studies ◽

Regulatory Region ◽

Airway Epithelial Cells ◽

Genome Wide Association Studies ◽

Airway Epithelial ◽

Allele Specific ◽

Enhancer Blocking ◽

Underlying Mechanisms

AbstractGenome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.

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