scholarly journals Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

2019 ◽  
Author(s):  
Stephen Watt ◽  
Louella Vasquez ◽  
Klaudia Walter ◽  
Alice L. Mann ◽  
Kousik Kundu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Autoimmune Disease ◽  
Inflammatory Response ◽  
Disease Susceptibility ◽  
Transcriptional Regulators ◽  
Genetic Associations ◽  
Cell Type ◽  
Immune Disease ◽  
Underlying Mechanisms

AbstractNeutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.

scholarly journals Effects of early life adversity on meningeal mast cells and proinflammatory gene expression in male and female Mus musculus

2021 ◽  
Author(s):  
Natalia Duque-Wilckens ◽  
Erika Sarno ◽  
Robby E. Teis ◽  
Frauke Stoelting ◽  
Sonia Khalid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Early Life ◽  
Inflammatory Markers ◽  
Disease Susceptibility ◽  
Early Life Adversity ◽  
Male And Female ◽  
The Brain

ABSTRACTExposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.

Investigation of anti-arthritic potential of ethanol extract of Hibiscus platinifolius

2020 ◽  
Vol 9 (1) ◽  
pp. 5-9
Author(s):  
Jogu Chandrudu
Keyword(s):  
Immune System ◽  
Autoimmune Disease ◽  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Ethanol Extract ◽  
The Body ◽  
Intervertebral Disks ◽  
Caudal Vertebrae ◽  
Medicinal Use ◽  
Serum Biochemical

Rheumatoid Arthritis is an autoimmune disease which causes chronic inflammation in the joints n even affects the healthy tissues in the body because their immune system attacks their body's tissues. This process creates an inflammatory response of the synovium, which is synovitis secondary to hyperplasia of the synovial cells. In their research, Locally available plants are verified on their therapeutic use. Arthritis is an autoimmune disease which causes chronic inflammation in the joints n even affects the healthy tissues in the body because their immune system attacks their body’s tissue. In Literature survey, it is revealed that the plant Hibiscus platinifolius (Malvaceae) is used as an ethnic folklore medicine for arthritis than other medicinal use. Primary inflammatory response consists of swelling of oedematous with multiple joints mainly in hind paws then within hours; it develops at the inoculation site. Later it involves the development of inflamed peri articular swelling in the limbs and of erythematous nodules and segmental radial swellings and ridgings which encircling the tail adjacent to the intervertebral disks of the caudal vertebrae. According to the reports, it has shown that the formation of bone was broadly reduced while bone resorption was increased in arthritic disease. In blood and liver, the FA activity increases then N-acetyltransferase (NAT) activity and it shows the effect not only on the serum biochemical parameters like SGOT, SGPT and ALP but also on haematological parameters such as RBC, WBC, Hb% and ESR.

Integrated analysis of transcriptome and histone modifications in granulosa cells during ovulation in female mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Yuichiro Shirafuta ◽  
Isao Tamura ◽  
Yasuyuki Ohkawa ◽  
Ryo Maekawa ◽  
Yumiko Doi-Tanaka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Inflammatory Response ◽  
Histone Modifications ◽  
Granulosa Cells ◽  
Cellular Functions ◽  
Lh Surge ◽  
Genome Wide ◽  
Ros Metabolism ◽  
Rapid Changes

Abstract The ovulatory luteinizing hormone (LH) surge induces rapid changes of gene expression and cellular functions in granulosa cells (GCs) undergoing luteinization. However, it remains unclear how the changes in genome-wide gene expression are regulated. H3K4me3 histone modifications are involved in rapid alteration of gene expression. In this study, we investigated genome-wide changes of transcriptome and H3K4me3 status in mouse GCs undergoing luteinization. GCs were obtained from mice treated with equine chorionic gonadotropin (eCG) before, 4 h and 12 h after human (h)CG injection. RNA-sequencing identified a number of up- and down-regulated genes, which could be classified into eight patterns according to the time-course changes of gene expression. Many genes were transiently up- or down-regulated at 4 h after hCG stimulation. Gene ontology terms associated with these genes included steroidogenesis, ovulation, COC expansion, angiogenesis, immune system, ROS metabolism, inflammatory response, metabolism and autophagy. The cellular functions of DNA repair and cell growth were newly identified as being activated during ovulation. ChIP-sequencing revealed a genome-wide and rapid change of H3K4me3 during ovulation. Integration of transcriptome and H3K4me3 data identified many H3K4me3-associated genes that are involved in steroidogenesis, ovulation, COC expansion, angiogenesis, inflammatory response, immune system, ROS metabolism, lipid and glucose metabolism, autophagy, and regulation of cell size. The present results suggest that genome-wide changes in H3K4me3 after the LH surge are associated with rapid changes in gene expression in GCs, which enables GCs acquire a lot of cellular functions within a short time that are required for ovulation and luteinization.

scholarly journals Gene expression variability in human and chimpanzee populations share common determinants

2020 ◽  
Author(s):  
Benjamin J. Fair ◽  
Lauren E. Blake ◽  
Abhishek Sarkar ◽  
Bryan J. Pavlovic ◽  
Claudia Cuevas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Comparative Analysis ◽  
Individual Variation ◽  
Disease Susceptibility ◽  
Expression Data ◽  
Cell Type ◽  
Orthologous Genes ◽  
Expression Variability ◽  
Gene Regulatory

AbstractInter-individual variation in gene expression has been shown to be heritable and it is often associated with differences in disease susceptibility between individuals. Many studies focused on mapping associations between genetic and gene regulatory variation, yet much less attention has been paid to the evolutionary processes that shape the observed differences in gene regulation between individuals in humans or any other primate. To begin addressing this gap, we performed a comparative analysis of gene expression variability and expression quantitative trait loci (eQTLs) in humans and chimpanzees, using gene expression data from primary heart samples. We found that expression variability in both species is often determined by non-genetic sources, such as cell-type heterogeneity. However, we also provide evidence that inter-individual variation in gene regulation can be genetically controlled, and that the degree of such variability is generally conserved in humans and chimpanzees. In particular, we found a significant overlap of orthologous genes associated with eQTLs in both species. We conclude that gene expression variability in humans and chimpanzees often evolves under similar evolutionary pressures.

scholarly journals Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system

2016 ◽  
Vol 113 (17) ◽  
pp. E2393-E2402 ◽  
Author(s):  
Alexis Vandenbon ◽  
Viet H. Dinh ◽  
Norihisa Mikami ◽  
Yohko Kitagawa ◽  
Shunsuke Teraguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Gene Expression Data ◽  
Cell Types ◽  
Treg Cells ◽  
Integrated Analysis ◽  
Expression Data ◽  
Batch Effects ◽  
Cell Type ◽  
Cell Type Specific

High-throughput gene expression data are one of the primary resources for exploring complex intracellular dynamics in modern biology. The integration of large amounts of public data may allow us to examine general dynamical relationships between regulators and target genes. However, obstacles for such analyses are study-specific biases or batch effects in the original data. Here we present Immuno-Navigator, a batch-corrected gene expression and coexpression database for 24 cell types of the mouse immune system. We systematically removed batch effects from the underlying gene expression data and showed that this removal considerably improved the consistency between inferred correlations and prior knowledge. The data revealed widespread cell type-specific correlation of expression. Integrated analysis tools allow users to use this correlation of expression for the generation of hypotheses about biological networks and candidate regulators in specific cell types. We show several applications of Immuno-Navigator as examples. In one application we successfully predicted known regulators of importance in naturally occurring Treg cells from their expression correlation with a set of Treg-specific genes. For one high-scoring gene, integrin β8 (Itgb8), we confirmed an association between Itgb8 expression in forkhead box P3 (Foxp3)-positive T cells and Treg-specific epigenetic remodeling. Our results also suggest that the regulation of Treg-specific genes within Treg cells is relatively independent of Foxp3 expression, supporting recent results pointing to a Foxp3-independent component in the development of Treg cells.

scholarly journals Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

2019 ◽  
Author(s):  
Clotilde Guyon ◽  
Nada Jmari ◽  
Francine Padonou ◽  
Yen-Chin Li ◽  
Olga Ucar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Autoimmune Disease ◽  
Epithelial Cells ◽  
Rnai Screen ◽  
Transcriptional Level ◽  
Transcript Isoforms ◽  
Transcript Stability ◽  
Medullary Epithelial Cells ◽  
Selection Of

AbstractThe ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3’end processing complex, suggesting they might impact transcript stability and levels through an effect on 3’UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3’UTR transcript isoforms in mTECs, a feature preceding Aire’s expression and correlated with the preferential selection of proximal polyA sites by the 3’end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3’UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.

scholarly journals Analysis of single cell data as it relates to aging and longevity

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 677-678
Author(s):  
Tanya Karagiannis ◽  
Todd Dowrey ◽  
Carlos Villacorta-Martin ◽  
George Murphy ◽  
Stefano Monti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Single Cell ◽  
Peripheral Blood ◽  
Age Groups ◽  
Cell Types ◽  
Cell Type ◽  
Younger Age ◽  
Cell Type Specific ◽  
Extreme Longevity

Abstract Age-related disability and diseases are known to be delayed in people living to 100 years or more. Changes in the immune system with age are known, including in cell type composition and gene expression differences. To further explore changes in extreme longevity subjects, we investigated peripheral blood immune system cell subpopulations across age and extreme longevity at a single cell resolution. We performed an integrative analysis of public scRNA-seq datasets to define consensus cell types of longevity and age, and classified cell types in our novel New England Centenarian Study dataset. We integrated these datasets together to investigate cell type specific differences at a composition and gene expression level. Our findings identified higher cell type diversity in extreme longevity subjects compared to younger age groups, but no significant difference among younger age groups demonstrating that overall composition differences are unique to longevity. We identified novel differences in myeloid and lymphocyte populations; Extreme longevity subjects have higher composition of CD14+ Monocytes, Natural Killer cells, and T gamma delta populations and lower composition of CD16+ Monocytes and dendritic populations. We characterized gene expression differences between extreme longevity and younger age groups and differences in aging across younger age groups. We found that extreme longevity cell type specific signatures overlapped with the aging signatures by at least 50%. We identified unique genes to extreme longevity that are enriched for pathways specific to immune activation and inflammation, suggesting a protective mechanism for centenarians through efficient activation and regulation of immune subpopulations in peripheral blood.

scholarly journals Gene expression variability in human and chimpanzee populations share common determinants

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Benjamin Jung Fair ◽  
Lauren E Blake ◽  
Abhishek Sarkar ◽  
Bryan J Pavlovic ◽  
Claudia Cuevas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Comparative Analysis ◽  
Individual Variation ◽  
Disease Susceptibility ◽  
Expression Data ◽  
Cell Type ◽  
Orthologous Genes ◽  
Expression Variability ◽  
Gene Regulatory

Inter-individual variation in gene expression has been shown to be heritable and is often associated with differences in disease susceptibility between individuals. Many studies focused on mapping associations between genetic and gene regulatory variation, yet much less attention has been paid to the evolutionary processes that shape the observed differences in gene regulation between individuals in humans or any other primate. To begin addressing this gap, we performed a comparative analysis of gene expression variability and expression quantitative trait loci (eQTLs) in humans and chimpanzees, using gene expression data from primary heart samples. We found that expression variability in both species is often determined by non-genetic sources, such as cell-type heterogeneity. However, we also provide evidence that inter-individual variation in gene regulation can be genetically controlled, and that the degree of such variability is generally conserved in humans and chimpanzees. In particular, we found a significant overlap of orthologous genes associated with eQTLs in both species. We conclude that gene expression variability in humans and chimpanzees often evolves under similar evolutionary pressures.

scholarly journals Neonatal genetics of gene expression reveal the origins of autoimmune and allergic disease risk

2019 ◽  
Author(s):  
Qin Qin Huang ◽  
Howard H. F. Tang ◽  
Shu Mei Teo ◽  
Scott C. Ritchie ◽  
Artika P. Nath ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Disease Risk ◽  
Allergic Diseases ◽  
Cell Types ◽  
Mendelian Randomisation ◽  
Genetic Associations ◽  
Cell Type ◽  
Genetics Of Gene Expression ◽  
Causal Variants

AbstractChronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we collected cord blood samples from a birth cohort and mapped expression quantitative trait loci (eQTLs) in resting monocytes and CD4+ T cells as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs were largely specific to cell type or stimulation, and response eQTLs were identified for 31% of genes with cis-eQTLs (eGenes) in monocytes and 52% of eGenes in CD4+ T cells. We identified trans-eQTLs and mapped cis regulatory factors which act as mediators of trans effects. There was extensive colocalisation of causal variants for cell type- and stimulation-specific neonatal cis-eQTLs and those of autoimmune and allergic diseases, in particular CTSH (Cathepsin H) which showed widespread colocalisation across diseases. Mendelian randomisation showed causal neonatal gene transcription effects on disease risk for BTN3A2, HLA-C and many other genes. Our study elucidates the genetics of gene expression in neonatal conditions and cell types as well as the aetiological origins of autoimmune and allergic diseases.

scholarly journals Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Clotilde Guyon ◽  
Nada Jmari ◽  
Francine Padonou ◽  
Yen-Chin Li ◽  
Olga Ucar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Autoimmune Disease ◽  
Epithelial Cells ◽  
Rnai Screen ◽  
Transcriptional Level ◽  
Transcript Isoforms ◽  
Transcript Stability ◽  
Medullary Epithelial Cells ◽  
Selection Of

The ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3’end processing complex, suggesting they might impact transcript stability and levels through an effect on 3’UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3’UTR transcript isoforms in mTECs, a feature preceding Aire’s expression and correlated with the preferential selection of proximal polyA sites by the 3’end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3’UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.

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