Faculty Opinions recommendation of Regenerant Arabidopsis lineages display a distinct genome-wide spectrum of mutations conferring variant phenotypes.

Current treatments for trauma-related disorders remain ineffective for many patients. Here, we modeled interindividual differences in post-therapy fear relapse with a novel ethologically relevant trauma recovery paradigm. After traumatic fear conditioning, rats underwent fear extinction while foraging in a large enriched arena, permitting the expression of a wide spectrum of behaviors, assessed by an automated pipeline. This multidimensional behavioral assessment revealed that post-conditioning fear response profiles clustered into two groups, respectively characterized by active vs. passive fear responses. After trauma, some animals expressed fear by freezing, while others darted, as if fleeing from danger. Remarkably, belonging to the darters or freezers group predicted differential vulnerability to fear relapse after extinction. Moreover, genome-wide transcriptional profiling revealed that these groups differentially regulated specific sets of genes, some of which have previously been implicated in anxiety and trauma-related disorders. Our results suggest that post-trauma behavioral phenotypes and the associated epigenetic landscapes can serve as markers of fear relapse susceptibility, and thus may be instrumental for future development of more effective treatments for psychiatric patients.

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Distinct, strict requirements for Gfi-1b in adult bone marrow red cell and platelet generation

Journal of Experimental Medicine ◽

10.1084/jem.20131065 ◽

2014 ◽

Vol 211 (5) ◽

pp. 909-927 ◽

Cited By ~ 37

Author(s):

Adlen Foudi ◽

Daniel J. Kramer ◽

Jinzhong Qin ◽

Denise Ye ◽

Anna-Sophie Behlich ◽

...

Keyword(s):

Bone Marrow ◽

Wide Spectrum ◽

Transcriptional Repressor ◽

Erythropoietin Receptor ◽

Red Cell ◽

Genome Wide ◽

Cytoplasmic Maturation ◽

Adult Bone

The zinc finger transcriptional repressor Gfi-1b is essential for erythroid and megakaryocytic development in the embryo. Its roles in the maintenance of bone marrow erythropoiesis and thrombopoiesis have not been defined. We investigated Gfi-1b’s adult functions using a loxP-flanked Gfi-1b allele in combination with a novel doxycycline-inducible Cre transgene that efficiently mediates recombination in the bone marrow. We reveal strict, lineage-intrinsic requirements for continuous adult Gfi-1b expression at two distinct critical stages of erythropoiesis and megakaryopoiesis. Induced disruption of Gfi-1b was lethal within 3 wk with severely reduced hemoglobin levels and platelet counts. The erythroid lineage was arrested early in bipotential progenitors, which did not give rise to mature erythroid cells in vitro or in vivo. Yet Gfi-1b−/− progenitors had initiated the erythroid program as they expressed many lineage-restricted genes, including Klf1/Eklf and Erythropoietin receptor. In contrast, the megakaryocytic lineage developed beyond the progenitor stage in Gfi-1b’s absence and was arrested at the promegakaryocyte stage, after nuclear polyploidization, but before cytoplasmic maturation. Genome-wide analyses revealed that Gfi-1b directly regulates a wide spectrum of megakaryocytic and erythroid genes, predominantly repressing their expression. Together our study establishes Gfi-1b as a master transcriptional repressor of adult erythropoiesis and thrombopoiesis.

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Developmental Dysplasia of Hip: Perspectives in Genetic Screening

Medical Sciences ◽

10.3390/medsci7040059 ◽

2019 ◽

Vol 7 (4) ◽

pp. 59 ◽

Cited By ~ 5

Author(s):

Zamborsky ◽

Kokavec ◽

Harsanyi ◽

Attia ◽

Danisovic

Keyword(s):

Psychological Health ◽

Screening Program ◽

Wide Spectrum ◽

Association Studies ◽

Modern Medicine ◽

Developmental Dysplasia ◽

Developmental Dysplasia Of Hip ◽

Lack Of Information ◽

Genome Wide ◽

Dysplasia Of The Hip

Development dysplasia of the hip (DDH) is a complex developmental disorder despite being a relatively common condition mainly caused by incompatibility of the femoral head and the abnormal joint socket. Development dysplasia of the hip describes a wide spectrum of disorders ranging from minor acetabular dysplasia to irreducible dislocation of the hip. Modern medicine still suffers from lack of information about screening and precise genetic examination. Genome wide linkage and association studies have brought significant progress to DDH diagnosis. Association studies managed to identify many candidate (susceptible) genes, such as PAPPA2, COL2A1, HOXD9, GDF-5, and TGFB1, which play a considerable role in the pathogenesis of DDH. Early detection of DDH has a big chance to help in preventing further disability and improve the psychological health and quality of life in those children. This emphasizes the importance to establish a universal screening program along with the genetic counseling.

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Shaping the nebulous enhancer in the era of high-throughput assays and genome editing

Briefings in Bioinformatics ◽

10.1093/bib/bbz030 ◽

2019 ◽

Vol 21 (3) ◽

pp. 836-850

Author(s):

Edwin Yu-Kiu Ho ◽

Qin Cao ◽

Mengting Gu ◽

Ricky Wai-Lun Chan ◽

Qiong Wu ◽

...

Keyword(s):

Genome Editing ◽

High Throughput ◽

Wide Spectrum ◽

Data Interpretation ◽

Future Studies ◽

Transcriptional Enhancers ◽

The Past ◽

Genome Wide ◽

Gray Areas ◽

Practical Implications

Abstract Since the 1st discovery of transcriptional enhancers in 1981, their textbook definition has remained largely unchanged in the past 37 years. With the emergence of high-throughput assays and genome editing, which are switching the paradigm from bottom-up discovery and testing of individual enhancers to top-down profiling of enhancer activities genome-wide, it has become increasingly evidenced that this classical definition has left substantial gray areas in different aspects. Here we survey a representative set of recent research articles and report the definitions of enhancers they have adopted. The results reveal that a wide spectrum of definitions is used usually without the definition stated explicitly, which could lead to difficulties in data interpretation and downstream analyses. Based on these findings, we discuss the practical implications and suggestions for future studies.

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RedChIP identifies noncoding RNAs associated with genomic sites occupied by Polycomb and CTCF proteins

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2116222119 ◽

2021 ◽

Vol 119 (1) ◽

pp. e2116222119

Author(s):

Alexey A. Gavrilov ◽

Rinat I. Sultanov ◽

Mikhail D. Magnitov ◽

Aleksandra A. Galitsyna ◽

Erdem B. Dashinimaev ◽

...

Keyword(s):

Chromatin Immunoprecipitation ◽

Binding Sites ◽

Wide Spectrum ◽

Noncoding Rnas ◽

Ctcf Binding ◽

Polycomb Repressive Complex 2 ◽

Proximity Ligation ◽

Chromatin Interactions ◽

Genome Wide ◽

Architectural Protein

Nuclear noncoding RNAs (ncRNAs) are key regulators of gene expression and chromatin organization. The progress in studying nuclear ncRNAs depends on the ability to identify the genome-wide spectrum of contacts of ncRNAs with chromatin. To address this question, a panel of RNA–DNA proximity ligation techniques has been developed. However, neither of these techniques examines proteins involved in RNA–chromatin interactions. Here, we introduce RedChIP, a technique combining RNA–DNA proximity ligation and chromatin immunoprecipitation for identifying RNA–chromatin interactions mediated by a particular protein. Using antibodies against architectural protein CTCF and the EZH2 subunit of the Polycomb repressive complex 2, we identify a spectrum of cis- and trans-acting ncRNAs enriched at Polycomb- and CTCF-binding sites in human cells, which may be involved in Polycomb-mediated gene repression and CTCF-dependent chromatin looping. By providing a protein-centric view of RNA–DNA interactions, RedChIP represents an important tool for studies of nuclear ncRNAs.

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The Combination of IFN β and TNF Induces an Antiviral and Immunoregulatory Program via Non-Canonical Pathways Involving STAT2 and IRF9

Cells ◽

10.3390/cells8080919 ◽

2019 ◽

Vol 8 (8) ◽

pp. 919 ◽

Cited By ~ 2

Author(s):

Mélissa K. Mariani ◽

Pouria Dasmeh ◽

Audray Fortin ◽

Elise Caron ◽

Mario Kalamujic ◽

...

Keyword(s):

Wide Spectrum ◽

Transcriptional Response ◽

Janus Kinase ◽

Transcriptional Analysis ◽

Interferon Stimulated Genes ◽

Gene Sets ◽

Genome Wide ◽

Canonical Pathways ◽

Transcriptional Complex ◽

Necrosis Factor

Interferon (IFN) β and Tumor Necrosis Factor (TNF) are key players in immunity against viruses. Compelling evidence has shown that the antiviral and inflammatory transcriptional response induced by IFNβ is reprogrammed by crosstalk with TNF. IFNβ mainly induces interferon-stimulated genes by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway involving the canonical ISGF3 transcriptional complex, composed of STAT1, STAT2, and IRF9. The signaling pathways engaged downstream of the combination of IFNβ and TNF remain elusive, but previous observations suggested the existence of a response independent of STAT1. Here, using genome-wide transcriptional analysis by RNASeq, we observed a broad antiviral and immunoregulatory response initiated in the absence of STAT1 upon IFNβ and TNF costimulation. Additional stratification of this transcriptional response revealed that STAT2 and IRF9 mediate the expression of a wide spectrum of genes. While a subset of genes was regulated by the concerted action of STAT2 and IRF9, other gene sets were independently regulated by STAT2 or IRF9. Collectively, our data supports a model in which STAT2 and IRF9 act through non-canonical parallel pathways to regulate distinct pool of antiviral and immunoregulatory genes in conditions with elevated levels of both IFNβ and TNF.

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Frequent Daytime Napping is Detrimental to Human Health: A phenotype-wide Mendelian Randomization Study

10.1101/2020.01.20.20017723 ◽

2020 ◽

Author(s):

Lanlan Chen ◽

Aowen Tian ◽

Zhipeng Liu ◽

Miaoran Zhang ◽

Xingchen Pan ◽

...

Keyword(s):

Health Outcomes ◽

Human Health ◽

Mendelian Randomization ◽

Wide Spectrum ◽

Association Studies ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Major Depressive ◽

Genome Wide ◽

The Uk

ABSTRACTBackgroundIt remains controversial whether daytime napping is beneficial for human health.ObjectiveTo examine the causal relationship between daytime napping and the risk for various human diseases.DesignPhenotype-wide Mendelian randomization study.SettingNon-UK Biobank cohorts reported in published genome-wide association studies (GWAS) provided the outcome phenotypes in the discovery stage. The UK Biobank cohort provided the outcome phenotypes in the validation stage.ParticipantsThe UK Biobank GWAS included 361,194 European-ancestry residents in the UK. Non-UKBB GWAS included various numbers of participants.ExposureSelf-reported daytime napping frequency.Main outcome measureA wide-spectrum of human health outcomes including obesity, major depressive disorder, and high cholesterol.MethodsWe examined the causal relationship between daytime napping frequency in the UK Biobank as exposure and a panel of 1,146 health outcomes reported in genome-wide association studies (GWAS), using a two-sample Mendelian randomization analysis. The significant findings were further validated in the UK Biobank health outcomes of 4,203 human traits and diseases. The causal effects were estimated using a fixed-effect inverse variance weighted model. MR-Egger intercept test was applied to detect horizontal pleiotropy, along with Cochran’s Q test to assess heterogeneity among the causal effects of IVs.FindingsThere were significant causal relationships between daytime napping frequency and a wide spectrum of human health outcomes. In particular, we validated that frequent daytime napping increased the risks of major depressive disorder, obesity and abnormal lipid profile.InterpretationThe current study showed that frequent daytime napping mainly had adverse impacts on physical and mental health. Cautions should be taken for health recommendations on daytime napping. Further studies are necessary to precisely define the best daytime napping strategies.

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Strong gene activation with genome-wide specificity using a new orthogonal CRISPR/Cas9-based Programmable Transcriptional Activator

10.1101/486068 ◽

2018 ◽

Cited By ~ 1

Author(s):

S Selma ◽

J Bernabé-Orts ◽

M Vazquez-Vilar ◽

B Diego ◽

M Ajenjo ◽

...

Keyword(s):

Regulatory Networks ◽

Target Genes ◽

Wide Spectrum ◽

Gene Activation ◽

Binding Activity ◽

Transcriptional Activators ◽

Endogenous Factors ◽

Activation Domains ◽

Dna Binding Activity ◽

Genome Wide

ABSTRACTSynthetic Biology (SynBio) aims at rewiring plant metabolic and developmental programs with orthogonal regulatory circuits. This endeavour requires new molecular tools able to interact with endogenous factors in a potent yet at the same time highly specific manner. A promising new class of SynBio tools that could play this function are the synthetic transcriptional activators based on CRISPR/Cas9 architecture, which combine autonomous activation domains (ADs) capable of recruiting the cell’s transcription machinery, with the easily customizable DNA-binding activity of nuclease-inactivated Cas9 protein (dCas9), creating so-called Programmable Transcriptional Activators (PTAs). In search for optimized dCas9-PTAs we performed a combinatorial analysis with seven different ADs arranged in four different protein/RNA architectures. This analysis resulted in the selection of a new dCas9-PTA with improved features as compared with previously reported activators. The new synthetic riboprotein, named dCasEV2.1, combines EDLL and VPR ADs using a multiplexable mutated version (v2.1) of the previously described aptamer-containing guide RNA2.0. We show here that dCasEV2.1 is a strong and wide spectrum activator, displaying variable activation levels depending on the basal activity of the target promoter. Maximum activation rates reaching up to 10000 fold were observed when targeting the NbDFR gene. Most remarkably, RNAseq analysis of dCasEV2.1-transformed N. benthamiana leaves revealed that the topmost activation capacity of dCasEV2.1 on target genes is accompanied with strict genome-wide specificity, making dCasEV2.1 an attractive tool for rewiring plant metabolism and regulatory networks.

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Using Full Genomic Information to Predict Disease: Breaking Down the Barriers Between Complex and Mendelian Diseases

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-083117-021136 ◽

2018 ◽

Vol 19 (1) ◽

pp. 289-301 ◽

Cited By ~ 3

Author(s):

Daniel M. Jordan ◽

Ron Do

Keyword(s):

Complex Disease ◽

Disease Risk ◽

Wide Spectrum ◽

Mendelian Disease ◽

Genomic Information ◽

Mendelian Diseases ◽

Genome Wide ◽

Whole Exome ◽

Large Populations ◽

Genomic Studies

While sequence-based genetic tests have long been available for specific loci, especially for Mendelian disease, the rapidly falling costs of genome-wide genotyping arrays, whole-exome sequencing, and whole-genome sequencing are moving us toward a future where full genomic information might inform the prognosis and treatment of a variety of diseases, including complex disease. Similarly, the availability of large populations with full genomic information has enabled new insights about the etiology and genetic architecture of complex disease. Insights from the latest generation of genomic studies suggest that our categorization of diseases as complex may conceal a wide spectrum of genetic architectures and causal mechanisms that ranges from Mendelian forms of complex disease to complex regulatory structures underlying Mendelian disease. Here, we review these insights, along with advances in the prediction of disease risk and outcomes from full genomic information.

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Genomic and Ancestral Variation Underlies the Severity of COVID-19 Clinical Manifestation in Individuals of European Descent

Life ◽

10.3390/life11090921 ◽

2021 ◽

Vol 11 (9) ◽

pp. 921

Author(s):

Priyanka Upadhyai ◽

Gokul Suresh ◽

Rahul Parit ◽

Ranajit Das

Keyword(s):

Multiple Testing ◽

Cholesterol Metabolism ◽

Wide Spectrum ◽

Severe Disease ◽

Control Group ◽

P Value ◽

European Descent ◽

Genome Wide ◽

A Genome ◽

Asymptomatic Subjects

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a wide spectrum of clinical phenotypes ranging from asymptomatic to symptomatic with mild or moderate presentation and severe disease. COVID-19 susceptibility, severity and recovery have demonstrated high variability worldwide. Variances in the host genetic architecture may underlie the inter-individual and population-scale differences in COVID-19 presentation. We performed a genome-wide association analysis employing the genotyping data from AncestryDNA for COVID-19 patients of European descent and used asymptomatic subjects as the control group. We identified 621 genetic variants that were significantly distinct between asymptomatic and acutely symptomatic COVID-19 patients (multiple-testing corrected p-value < 0.001). These variants were found to be associated with pathways governing host immunity, such as interferon, interleukin and cytokine signalling, and known COVID-19 comorbidities, such as obesity and cholesterol metabolism. Further, our ancestry analysis revealed that the asymptomatic COVID-19 patients possess discernibly higher proportions of the Ancestral North Eurasian (ANE) and Eastern Hunter-Gatherer (EHG) ancestry, which was introduced to Europe through Bell Beaker culture (Yamnaya related) and lower fractions of Western Hunter-Gatherer (WHG) ancestry, while severely symptomatic patients have higher fractions of WHG and lower ANE/EHG ancestral components, thereby delineating the likely ancestral differences between the two groups.

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