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

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

10.1101/837880 ◽

2019 ◽

Cited By ~ 1

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.

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An enhancer region determines hSP-B gene expression in bronchiolar and ATII epithelial cells in transgenic mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00280.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. L481-L488 ◽

Cited By ~ 10

Author(s):

Li Yang ◽

Angela Naltner ◽

Allison Kreiner ◽

Dong Yan ◽

Angelynn Cowen ◽

...

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Transgenic Mice ◽

Transgenic Mouse ◽

Lung Development ◽

Alveolar Type ◽

Transcriptional Level ◽

Lacz Gene ◽

Type Ii ◽

Enhancer Region

Regulation of the surfactant protein B gene (SP-B) is developmentally controlled and highly tissue specific. To elucidate the SP-B gene temporal/spatial expression pattern in lung development at the transcriptional level, a transgenic mouse model line carrying the human SP-B (hSP-B) 1.5-kb 5′-flanking regulatory region and the lacZ gene was established. Expression of hSP-B 1.5-kb lacZ gene started at the onset of lung formation [embryonic day 9 (E9)] and was restricted to epithelial cells throughout prenatal and postnatal lung development. In the adult lung, hSP-B 1.5-kb lacZ gene expression was restricted to bronchiolar and alveolar type II epithelial cells. In lung explant culturing studies, the hSP-B 1.5-kb lacZ gene was highly expressed in newly formed epithelial tubules during the respiratory branching process. In a second transgenic mouse line, an enhancer region, which binds to thyroid transcription factor-1, retinoic acid receptor, signal transducers and activators of transcription 3, and nuclear receptor coactivators (SRC-1, ACTR, TIF2, and CBP/p300), was deleted from the hSP-B 1.5-kb lacZ gene. The deletion abolished hSP-B lacZ gene expression in bronchiolar epithelial cells and significantly reduced its expression level in alveolar type II epithelial cells in transgenic mice.

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In-Silico Study of Immune System Associated Genes in Case of Type-2 Diabetes With Insulin Action and Resistance, and/or Obesity

Frontiers in Endocrinology ◽

10.3389/fendo.2021.641888 ◽

2021 ◽

Vol 12 ◽

Author(s):

Basmah Medhat Eldakhakhny ◽

Hadeel Al Sadoun ◽

Hani Choudhry ◽

Mohammad Mobashir

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Immune System ◽

Genetic Alterations ◽

Transcriptional Level ◽

T Cell Signaling ◽

Tcr Signaling ◽

Major Barrier ◽

Diabetes And Obesity

Type-2 diabetes and obesity are among the leading human diseases and highly complex in terms of diagnostic and therapeutic approaches and are among the most frequent and highly complex and heterogeneous in nature. Based on epidemiological evidence, it is known that the patients suffering from obesity are considered to be at a significantly higher risk of type-2 diabetes. There are several pieces of evidence that support the hypothesis that these diseases interlinked and obesity may aggravate the risk(s) of type-2 diabetes. Multi-level unwanted alterations such as (epi-) genetic alterations, changes at the transcriptional level, and altered signaling pathways (receptor, cytoplasmic, and nuclear level) are the major sources that promote several complex diseases, and such a heterogeneous level of complexity is considered as a major barrier in the development of therapeutics. With so many known challenges, it is critical to understand the relationships and the shared causes between type-2 diabetes and obesity, and these are difficult to unravel and understand. For this purpose, we have selected publicly available datasets of gene expression for obesity and type-2 diabetes, have unraveled the genes and the pathways associated with the immune system, and have also focused on the T-cell signaling pathway and its components. We have applied a simplified computational approach to understanding differential gene expression and patterns and the enriched pathways for obesity and type-2 diabetes. Furthermore, we have also analyzed genes by using network-level understanding. In the analysis, we observe that there are fewer genes that are commonly differentially expressed while a comparatively higher number of pathways are shared between them. There are only 4 pathways that are associated with the immune system in case of obesity and 10 immune-associated pathways in case of type-2 diabetes, and, among them, only 2 pathways are commonly altered. Furthermore, we have presented SPNS1, PTPN6, CD247, FOS, and PIK3R5 as the overexpressed genes, which are the direct components of TCR signaling.

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Mechanism of dexamethasone-mediated interleukin-8 gene suppression in cultured airway epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.1.l107 ◽

2001 ◽

Vol 280 (1) ◽

pp. L107-L115 ◽

Cited By ~ 36

Author(s):

Mary Mann-Jong Chang ◽

Maya Juarez ◽

Dallas M. Hyde ◽

Reen Wu

Keyword(s):

Gene Expression ◽

Protein Synthesis ◽

Epithelial Cells ◽

Actinomycin D ◽

Airway Epithelial Cells ◽

Interleukin 8 ◽

Transcriptional Level ◽

Dependent Manner ◽

Airway Epithelial ◽

New Protein

The effects of dexamethasone, a glucocorticoid analog, on interleukin 8 (IL-8) gene expression were studied in cultures of primary human tracheobronchial epithelial cells and an immortalized human bronchial epithelial cell line, HBE1 cells. Dexamethasone inhibited IL-8 mRNA and protein expression in a concentration- and time-dependent manner. The inhibition did not occur at the transcriptional level since both nuclear run-on activity and IL-8 promoter-reporter gene expression assay revealed no significant effect. Instead, there was a change in IL-8 mRNA stability in dexamethasone-treated cultures. Under actinomycin D treatment, IL-8 mRNA was quite stable in dexamethasone-depleted cultures, while in dexamethasone-pretreated cultures, IL-8 message was rapidly degraded within the first hour, then leveled off. When dexamethasone and actinomycin D were added simultaneously to dexamethasone-depleted cultures, IL-8 mRNA remained rather stable. When cycloheximide was used to inhibit new protein synthesis, dexamethasone-dependent inhibition was not observed. These results suggest that a posttranscriptional mechanism, which requires dexamethasone-dependent new protein synthesis, is involved in the regulation of IL-8 mRNA by dexamethasone in airway epithelial cells.

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PDGFRα-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches

Blood ◽

10.1182/blood-2006-05-023143 ◽

2006 ◽

Vol 109 (3) ◽

pp. 954-960 ◽

Cited By ~ 60

Author(s):

William E. Jenkinson ◽

Simona W. Rossi ◽

Sonia M. Parnell ◽

Eric J. Jenkinson ◽

Graham Anderson

Keyword(s):

T Cells ◽

T Cell ◽

Epithelial Cells ◽

Growth Factor Receptor ◽

Thymic Epithelial Cells ◽

Thymic Tissue ◽

Mhc Molecules ◽

Histocompatibility Complex ◽

Medullary Epithelial Cells ◽

Selection Of

Abstract The thymus provides a specialized site for the production of T cells capable of recognizing foreign antigens in the context of self–major histocompatibility complex (MHC) molecules. During development, the thymus arises from an epithelial rudiment containing bipotent progenitors that differentiate into distinct cortical and medullary epithelial cells to regulate the maturation and selection of self-tolerant CD4+ and CD8+ T cells. In addition to their differentiation, thymic epithelial cells undergo cellular expansion to ensure that sufficient intrathymic cellular niches are available to support the large number of immature thymocytes required to form a self-tolerant T-cell pool. Thus, intrathymic T-cell production is intimately linked to the formation and availability of niches within thymic microenvironments. Here, we show the increase in intrathymic niches caused by the proliferation of the epithelium in the developing thymus is temporally regulated, and correlates with the presence of a population of fetal thymic mesenchyme defined by platelet-derived growth factor receptor α (PDGFRα) expression. Depletion of PDGFRα+ mesenchyme from embryonic thymi prior to their transplantation to ectopic sites results in the formation of functional yet hypoplastic thymic tissue. In summary, we highlight a specialized role for PDGFRα+ fetal mesenchyme in the thymus by determining availability of thymic niches through the regulation of thymic epithelial proliferation.

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Regulation of mucin gene expression in human tracheobronchial epithelial cells by thyroid hormone

Biochemical Journal ◽

10.1042/bj3530727 ◽

2001 ◽

Vol 353 (3) ◽

pp. 727-734 ◽

Cited By ~ 6

Author(s):

Thomas GRAY ◽

Paul NETTESHEIM ◽

Carol BASBAUM ◽

Ja-Seok KOO

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

Epithelial Cells ◽

Airway Epithelial Cells ◽

Luciferase Reporter ◽

Transcriptional Level ◽

Airway Epithelial ◽

Retinoid Receptor ◽

Western Blots ◽

Receptor Proteins

We reported previously that the expression of the gene encoding MUC5AC mucin in human airway epithelial cells is controlled by retinoic acid via the retinoic acid receptor (RAR)-α and that 3,3′,5-tri-iodothyronine (T3) inhibits the expression of MUC5AC. The purpose of the present study was to identify mechanisms mediating the effect of T3. T3 has been shown to inhibit gene expression via several mechanisms, either by enhancing or repressing the transcription of target genes or by the regulation of post-transcriptional events. Results showed that T3 strongly inhibited MUC5AC-driven luciferase activity in normal human tracheobronchial epithelial cells that had been transiently transfected with a MUC5AC–luciferase reporter construct; however, it did not affect MUC5AC mRNA stability. These results indicate that T3 suppresses MUC5AC expression at the transcriptional level. An analysis of deletion constructs showed that deletion of the region downstream of 3kb resulted in markedly decreased levels of MUC5AC transcription in the absence of T3 (i.e. under control conditions) as well as a loss of responsiveness to the inhibitory effects of T3. This suggests that this region might contain elements important for the activation as well as the repression of MUC5AC transcription. To determine whether T3 modulates retinoic-acid-dependent MUC5AC transcription via an alteration in the abundance of retinoid receptor proteins, we examined the type and abundance of these receptors in nuclear extracts of airway epithelial cells grown in the presence or absence of T3. Western blots showed that T3 markedly decreased several types of retinoid receptor while not affecting T3 receptor proteins. Consistent with this finding were gel-shift assays revealing a decrease in RAR–retinoic acid response element complexes obtained from T3-treated cells. We propose that T3 might inhibit retinoid-dependent MUC5AC expression by decreasing retinoid receptor levels and thereby decreasing the transcriptional activation of this gene for mucins.

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

10.1101/620260 ◽

2019 ◽

Cited By ~ 1

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.

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Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1009265107 ◽

2010 ◽

Vol 107 (45) ◽

pp. 19426-19431 ◽

Cited By ~ 33

Author(s):

L.-O. Tykocinski ◽

A. Sinemus ◽

E. Rezavandy ◽

Y. Weiland ◽

D. Baddeley ◽

...

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Epigenetic Regulation ◽

Medullary Epithelial Cells ◽

Promiscuous Gene Expression

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Electron microscope study of the secretory activity of epithelial cells in embryonic thymus

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010015945x ◽

1990 ◽

Vol 48 (3) ◽

pp. 382-383

Author(s):

H. Alasam

Keyword(s):

Cell Differentiation ◽

T Cell ◽

Epithelial Cells ◽

Electron Density ◽

Secretory Activity ◽

T Cell Differentiation ◽

High Electron ◽

Transmission Electron ◽

Medullary Epithelial Cells ◽

Thymic Factor

The possibility that intrathymic T-cell differentiation involves stem cell-lymphoid interactions in embryos led us to study the ultrastructure of epithelial cell in normal embryonic thymus. Studies in adult thymus showed that it produces several peptides that induce T-cell differentiation. Several of them have been chemically characterized, such as thymosin α 1, thymopoietin, thymic humoral factor or the serum thymic factor. It was suggested that most of these factors are secreted by populations of A and B-epithelial cells.Embryonic materials were obtained from inbred matings of Swiss Albino mice. Thymuses were disected from embryos 17 days old and prepared for transmission electron microscopy. Our studies showed that embryonic thymus at this stage contains undifferentiated and differentiated epithelial cells, large lymphoblasts, medium and few small lymphocytes (Fig. 5). No differences were found between cortical and medullary epithelial cells, in contrast to the findings of Van Vliet et al,. Epithelial cells were mostly of the A-type with low electron density in both cytoplasm and nucleus. However few B-type with high electron density were also found (Fig. 7).

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