scholarly journals Transposable elements have contributed human regulatory regions that are activated upon bacterial infection

2020 ◽  
Vol 375 (1795) ◽  
pp. 20190332 ◽  
Author(s):  
Lucia Bogdan ◽  
Luis Barreiro ◽  
Guillaume Bourque
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Transposable Elements ◽  
Cell Activation ◽  
Immune Cell ◽  
Regulation Of Gene Expression ◽  
Interferon Response ◽  
Human Interferon ◽  
Trait Locus ◽  
Accessible Chromatin

Transposable elements (TEs) are increasingly recognized as important contributors to mammalian regulatory systems. For instance, they have been shown to play a role in the human interferon response, but their involvement in other mechanisms of immune cell activation remains poorly understood. Here, we investigated the profile of accessible chromatin enhanced in stimulated human macrophages using ATAC-seq to assess the role of different TE subfamilies in regulating gene expression following an immune response. We found that both previously identified and new repeats belonging to the MER44, THE1, Tigger3 and MLT1 families provide 14 subfamilies that are enriched in differentially accessible chromatin and found near differentially expressed genes. These TEs also harbour binding motifs for several candidate transcription factors, including important immune regulators AP-1 and NF-κB, present in 96% of accessible MER44B and 83% of THE1C instances, respectively. To more directly assess their regulatory potential, we evaluated the presence of these TEs in regions putatively affecting gene expression, as defined by quantitative trait locus (QTL) analysis, and found that repeats are also contributing to accessible elements near QTLs. Together, these results suggest that a number of TE families have contributed to the regulation of gene expression in the context of the immune response to infection in humans. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

scholarly journals Transposable elements have contributed human regulatory regions that are activated upon bacterial infection

2019 ◽  
Author(s):  
Lucia Bogdan ◽  
Luis Barreiro ◽  
Guillaume Bourque
Keyword(s):  
Transposable Elements ◽  
Cell Activation ◽  
Immune Cell ◽  
Interferon Response ◽  
Human Interferon ◽  
Binding Motifs ◽  
Immune Cell Activation ◽  
Regulatory Systems ◽  
Trait Locus ◽  
Accessible Chromatin

ABSTRACTTransposable elements (TEs) are increasingly recognized as important contributors to mammalian regulatory systems. For instance, they have been shown to play a role in the human interferon response. However, their involvement in other mechanisms of immune cell activation remains poorly understood. We investigated the profile of accessible chromatin enhanced in stimulated human macrophages using ATAC-Seq to assess the role of different TE subfamilies in regulating the immune response. We found that both previously identified and new repeats belonging to the MER44, THE1, Tigger3 and MLT1 families provide 14 subfamilies that are enriched in differentially accessible chromatin and found near differentially expressed genes. These TEs also harbour binding motifs for several candidate transcription factors, including important immune regulators AP-1 and NF-kB, present in 96% of accessible MER44B and 83% of THE1C instances, respectively. To more directly assess their regulatory potential, we evaluated their presence in regions putatively affecting gene expression, as defined by quantitative trait locus (QTL) analysis, and find that repeats are also contributing to accessible elements near QTLs. Together, these results suggest that a number of TE families have contributed to the regulation of the immunogenomic response to infection in humans.

TLR2-mediated innate immune priming boosts lung anti-viral immunity

2020 ◽  
pp. 2001584
Author(s):  
Jason Girkin ◽  
Su-Ling Loo ◽  
Camille Esneau ◽  
Steven Maltby ◽  
Francesca Mercuri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Innate Immunity ◽  
Viral Load ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Immune Priming ◽  
Tlr2 Activation

Research questionAssessment of whether TLR2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases.MethodsWe employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III IFN production, as well as the lung tissue and epithelial cell immune transcriptome.ResultsWe show in vivo, that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7-days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1-day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7-days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro, INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for NF-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response.ConclusionAirway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.

scholarly journals PD-L1 and tumor-associated macrophages in de novo DLBCL

2019 ◽  
Vol 3 (4) ◽  
pp. 531-540 ◽  
Author(s):  
Ronald McCord ◽  
Christopher R. Bolen ◽  
Hartmut Koeppen ◽  
Edward E. Kadel ◽  
Mikkel Z. Oestergaard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Activation ◽  
Immune Cell ◽  
De Novo ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Staining Procedure ◽  
Immune Cell Activation ◽  
Improved Outcomes ◽  
Risk Patients

Abstract Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are important negative regulators of immune cell activation. Therapeutically targeting PD-1/PD-L1 in diffuse large B-cell lymphoma (DLBCL) patients with a single agent has limited activity, meriting a deeper understanding of this complex biology and of available PD-L1 clinical assays. In this study, we leveraged 2 large de novo DLBCL phase 3 trials (GOYA and MAIN) to better understand the biologic and clinical relevance of PD-L1 in de novo DLBCL. PD-L1 was expressed on myeloid cells in 85% to 95% of DLBCL patients (depending on staining procedure), compared with 10% on tumor cells, and correlated with macrophage gene expression. PD-L1 did not identify high-risk patients in de novo DLBCL; it correlated with STAT3, macrophage gene expression, and improved outcomes among a subset of patients. These results may help identify immunologically distinct DLBCL subsets relevant for checkpoint blockade. GOYA and MAIN trials were registered at www.clinicaltrials.gov as #NCT01287741 and #NCT00486759, respectively.

scholarly journals Roles of Transposable Elements in the Different Layers of Gene Expression Regulation

2019 ◽  
Vol 20 (22) ◽  
pp. 5755 ◽  
Author(s):  
Denise Drongitis ◽  
Francesco Aniello ◽  
Laura Fucci ◽  
Aldo Donizetti
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Gene Expression Regulation ◽  
Regulation Of Gene Expression ◽  
Chromatin Modification ◽  
Essential Element ◽  
Protein Translation ◽  
Expression Regulation ◽  
Molecular Processes ◽  
Eukaryotic Genomes

The biology of transposable elements (TEs) is a fascinating and complex field of investigation. TEs represent a substantial fraction of many eukaryotic genomes and can influence many aspects of DNA function that range from the evolution of genetic information to duplication, stability, and gene expression. Their ability to move inside the genome has been largely recognized as a double-edged sword, as both useful and deleterious effects can result. A fundamental role has been played by the evolution of the molecular processes needed to properly control the expression of TEs. Today, we are far removed from the original reductive vision of TEs as “junk DNA”, and are more convinced that TEs represent an essential element in the regulation of gene expression. In this review, we summarize some of the more recent findings, mainly in the animal kingdom, concerning the active roles that TEs play at every level of gene expression regulation, including chromatin modification, splicing, and protein translation.

scholarly journals REDIportal: millions of novel A-to-I RNA editing events from thousands of RNAseq experiments

2020 ◽  
Vol 49 (D1) ◽  
pp. D1012-D1019 ◽  
Author(s):  
Luigi Mansi ◽  
Marco Antonio Tangaro ◽  
Claudio Lo Giudice ◽  
Tiziano Flati ◽  
Eli Kopel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Comparative Genomics ◽  
Rna Editing ◽  
Innate Immune Response ◽  
Transcriptome Sequencing ◽  
Regulation Of Gene Expression ◽  
Innate Immune ◽  
Neurotransmitter Receptors ◽  
Eukaryotic Organisms

Abstract RNA editing is a relevant epitranscriptome phenomenon able to increase the transcriptome and proteome diversity of eukaryotic organisms. ADAR mediated RNA editing is widespread in humans in which millions of A-to-I changes modify thousands of primary transcripts. RNA editing has pivotal roles in the regulation of gene expression or modulation of the innate immune response or functioning of several neurotransmitter receptors. Massive transcriptome sequencing has fostered the research in this field. Nonetheless, different aspects of the RNA editing biology are still unknown and need to be elucidated. To support the study of A-to-I RNA editing we have updated our REDIportal catalogue raising its content to about 16 millions of events detected in 9642 human RNAseq samples from the GTEx project by using a dedicated pipeline based on the HPC version of the REDItools software. REDIportal now allows searches at sample level, provides overviews of RNA editing profiles per each RNAseq experiment, implements a Gene View module to look at individual events in their genic context and hosts the CLAIRE database. Starting from this novel version, REDIportal will start collecting non-human RNA editing changes for comparative genomics investigations. The database is freely available at http://srv00.recas.ba.infn.it/atlas/index.html.

scholarly journals The genetic basis of evolutionary change in gene expression levels

2010 ◽  
Vol 365 (1552) ◽  
pp. 2581-2590 ◽  
Author(s):  
J. J. Emerson ◽  
Wen-Hsiung Li
Keyword(s):  
Gene Expression ◽  
Genetic Basis ◽  
Regulation Of Gene Expression ◽  
Specific Expression ◽  
Genetic Changes ◽  
Expression Variation ◽  
Regulatory Variation ◽  
Global Mapping ◽  
History Of ◽  
Trait Locus

The regulation of gene expression is an important determinant of organismal phenotype and evolution. However, the widespread recognition of this fact occurred long after the synthesis of evolution and genetics. Here, we give a brief sketch of thoughts regarding gene regulation in the history of evolution and genetics. We then review the development of genome-wide studies of gene regulatory variation in the context of the location and mode of action of the causative genetic changes. In particular, we review mapping of the genetic basis of expression variation through expression quantitative trait locus studies and measuring the cis / trans component of expression variation in allele-specific expression studies. We conclude by proposing a systematic integration of ideas that combines global mapping studies, cis / trans tests and modern population genetics methodologies, in order to directly estimate the forces acting on regulatory variation within and between species.

Association of phosphatidylinositol 3-kinase (PI3K) pathway activation with increased immune checkpoint expression in colorectal cancer (CRC) patients.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 653-653 ◽  
Author(s):  
Maliha Nusrat ◽  
Jason Roszik ◽  
Riham Katkhuda ◽  
David Menter ◽  
Kanwal Pratap Singh Raghav ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Protein Expression ◽  
Immune Cell ◽  
Early Stage ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Pik3ca Mutations ◽  
The Impact

653 Background: PI3K pathway is a known modulator of anti-tumor immune response and is frequently activated in CRC through genetic alterations such as PTEN loss (PTENloss) and PIK3CA mutations (PIK3CAmut). This study aims to determine the impact of these alterations on immune cell infiltration, priming and activation in early stage CRC patients (pts). Methods: Immune infiltrates and checkpoints were evaluated using quantitative immunohistochemistry (IHC) on primary CRC (N = 59) for both center of tumor (CT) and invasive margin (IM). Pts were evaluated by presence or absence of either PTENloss or PIK3CAmut (collectively termed PI3K pathway alterations). Microsatellite unstable (MSI) and stable (MSS) tumors were analyzed separately. Clinicopathologic data was examined for potential associations with PI3K pathway alterations. Separately, mRNA data (Agilent) was obtained for immune related genes from an internal cohort with PTEN and PIK3CA annotation (N = 73). Results: 59 pts comprised IHC cohort (40 MSS, 19 MSI); 23 pts (39%) had PTENloss or PIK3CAmut. In Agilent cohort, 16 of 73 pts (22%) had PI3K pathway alterations. In MSS CRC, these alterations were more common in CMS1 (p = 0.03), on right side (p = 0.048) and with peritumoral lymphocytes (p = 0.031). MSS pts with PI3K pathway alterations had higher PD1 protein expression (p = 0.04), 2.1 and 2.3 times increased density of CD3+ (p = 0.01) and CD8+ (p = 0.04) cells respectively, and higher Granzyme B protein expression (p = 0.04) in the CT. These pts also had higher PDL1 gene expression (p = 0.046). MSS CRC pts with PIK3CAmut similarly had 2 times more PDL1 protein expression in epithelial cells of the IM (p = 0.01). Alternate checkpoints were also increased in pts with PI3K pathway alterations, including higher protein expression of LAG3 in CT (P = 0.046) and higher gene expression of CTLA4, TIM3, and TIGIT (P < 0.05 for all). Conclusions: PI3K pathway activated MSS CRC is associated with increased immune engagement, but also upregulation of key immune checkpoints in early stage tumors resulting in an ineffective immune response. Combination of PI3K pathway inhibition with immunotherapy merits investigation in this subset of pts.

Mammalian genome evolution as a result of epigenetic regulation of transposable elements

2014 ◽  
Vol 5 (3) ◽  
pp. 183-194 ◽  
Author(s):  
Reuben M. Buckley ◽  
David L. Adelson
Keyword(s):  
Gene Expression ◽  
Transposable Elements ◽  
Epigenetic Regulation ◽  
Dna Sequences ◽  
Defense Mechanisms ◽  
Regulatory Networks ◽  
Regulation Of Gene Expression ◽  
Epigenetic Marks ◽  
Rna Molecules ◽  
Mammalian Genomes

AbstractTransposable elements (TEs) make up a large proportion of mammalian genomes and are a strong evolutionary force capable of rewiring regulatory networks and causing genome rearrangements. Additionally, there are many eukaryotic epigenetic defense mechanisms able to transcriptionally silence TEs. Furthermore, small RNA molecules that target TE DNA sequences often mediate these epigenetic defense mechanisms. As a result, epigenetic marks associated with TE silencing can be reestablished after epigenetic reprogramming – an event during the mammalian life cycle that results in widespread loss of parental epigenetic marks. Furthermore, targeted epigenetic marks associated with TE silencing may have an impact on nearby gene expression. Therefore, TEs may have driven species evolution via their ability to heritably alter the epigenetic regulation of gene expression in mammals.

Sign in / Sign up

Export Citation Format

Share Document