scholarly journals The 3D enhancer network of the developing T cell genome is controlled by SATB1

2021 ◽  
Author(s):  
Tomas Zelenka ◽  
Antonios Klonizakis ◽  
Despina Tsoukatou ◽  
Sören Franzenburg ◽  
Petros Tzerpos ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Genome Organization ◽  
Molecular Mechanisms ◽  
Regulatory Elements ◽  
Conditional Knockout ◽  
Specific Factor ◽  
Specific Gene ◽  
Gene Promoters ◽  
Tissue Specific

Mechanisms of tissue-specific gene expression regulation via spatial coordination of gene promoters and distal regulatory elements are still poorly understood. We investigated the 3D genome organization of developing murine T cells and identified SATB1, a tissue-specific genome organizer, enriched at the anchors of promoter-enhancer chromatin loops. We assessed the function of SATB1 in T cell chromatin organization and compared it to the conventional genome organizer CTCF. SATB1 builds a more refined layer of genome organization upon a CTCF scaffold. To understand the regulatory implications of SATB1 loopscape structure, we generated Satb1fl/flCd4-Cre+ (Satb1 cKO) conditional knockout animals which suffered from autoimmunity. We aimed to identify molecular mechanisms responsible for the deregulation of the immune system in Satb1 cKO animals. H3K27ac HiChIP and Hi-C experiments indicated that SATB1 primarily mediates promoter-enhancer loops affecting master regulator genes (such as Bcl6), the T cell receptor locus and adhesion molecule genes, collectively being critical for cell lineage specification and immune system homeostasis. Our findings unravel the function of a tissue-specific factor that controls transcription programs, via spatial chromatin arrangements complementary to the chromatin structure imposed by ubiquitously expressed genome organizers.

scholarly journals Identification of cis-acting regulatory elements controlling interleukin-4 gene expression in T cells: roles for NF-Y and NF-ATc.

1993 ◽  
Vol 13 (8) ◽  
pp. 4793-4805 ◽  
Author(s):  
S J Szabo ◽  
J S Gold ◽  
T L Murphy ◽  
K M Murphy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Promoter Activity ◽  
Regulatory Elements ◽  
Interleukin 4 ◽  
Specific Factor ◽  
Gene Promoters ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Cis Acting

Activity of the murine interleukin-4 (IL-4) promoter was localized to several cis-acting elements present within the first 300 bp from the transcriptional initiation site. Five repeated elements, P0 to P4, that share the common consensus ATTTTCCNNT were located between -40 and -250, and each was shown to interact with the T-cell-specific factor NF(P). These distinct P sites appear functionally interchangeable and cooperatively confer cyclosporin A-sensitive and ionomycin-inducible promoter activity. NF(P) may be closely related to the cytoplasmic component of NF-AT (nuclear factor of activated T cells), a T-cell-specific factor essential for IL-2 gene transcription, as judged from indistinguishable molecular weights and protease fragmentation patterns of UV-photolabeled factors. Also, we identified an element in the IL-4 promoter with homology to the Y box common to all major histocompatibility complex class II gene promoters. Our data show that the IL-4 promoter Y box -114CTGATTGG-107 significantly enhances overall promoter activity, since point mutations within this element diminish promoter activity by 85%. The factor binding this region is indistinguishable from the cloned nuclear factor NF-Y, as judged from interactions with specific anti-NF-Y monoclonal and polyclonal antibodies. Last, we point out the presence of two sites that share sequence identity to the OAP region of the ARRE-1 site within the IL-2 promoter (K. S. Ullman, W. M. Flanagan, C. A. Edwards, and G. R. Crabtree, Science 254:558-562, 1991). These regions, -85GTGTAATA-78 and -245GTGTAATT-238, reside adjacent to the NF(P) binding sites P1 and P4 and bind a distinct nuclear factor.

scholarly journals Tissue-specific gene expression in the pituitary: the glycoprotein hormone alpha-subunit gene is regulated by a gonadotrope-specific protein.

1992 ◽  
Vol 12 (5) ◽  
pp. 2143-2153 ◽  
Author(s):  
F Horn ◽  
J J Windle ◽  
K M Barnhart ◽  
P L Mellon
Keyword(s):  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Alpha Subunit ◽  
Specific Factor ◽  
Specific Gene ◽  
Homeodomain Protein ◽  
Subunit Gene ◽  
Glycoprotein Hormone ◽  
Specific Expression ◽  
Tissue Specific

The molecular mechanisms for the development of multiple distinct endocrine cell types in the anterior pituitary have been an area of intensive investigation. Though the homeodomain protein Pit-1/GHF-1 is known to be involved in differentiation of the somatotrope and lactotrope lineages, which produce growth hormone and prolactin, respectively, little is known of the transcriptional regulators important for the gonadotrope cell lineage, which produces the glycoprotein hormones luteinizing hormone and follicle-stimulating hormone. Using transgenic mice and transfection into a novel gonadotrope lineage cell line, we have identified a regulatory element that confers gonadotrope-specific expression to the glycoprotein hormone alpha-subunit gene. A tissue-specific factor that binds to this element is purified and characterized as a 54-kDa protein which is present uniquely in cells of the gonadotrope lineage and is not Pit-1/GHF-1. The human and equine alpha-subunit genes are also expressed in placental cells. However, the previously characterized placental transcription factors designated TSEB and alpha-ACT are not found in the pituitary gonadotrope cells, indicating that independent mechanisms confer expression of these genes in the two different tissues.

Tissue-specific gene expression in the pituitary: the glycoprotein hormone alpha-subunit gene is regulated by a gonadotrope-specific protein

1992 ◽  
Vol 12 (5) ◽  
pp. 2143-2153
Author(s):  
F Horn ◽  
J J Windle ◽  
K M Barnhart ◽  
P L Mellon
Keyword(s):  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Alpha Subunit ◽  
Specific Factor ◽  
Specific Gene ◽  
Homeodomain Protein ◽  
Subunit Gene ◽  
Glycoprotein Hormone ◽  
Specific Expression ◽  
Tissue Specific

The molecular mechanisms for the development of multiple distinct endocrine cell types in the anterior pituitary have been an area of intensive investigation. Though the homeodomain protein Pit-1/GHF-1 is known to be involved in differentiation of the somatotrope and lactotrope lineages, which produce growth hormone and prolactin, respectively, little is known of the transcriptional regulators important for the gonadotrope cell lineage, which produces the glycoprotein hormones luteinizing hormone and follicle-stimulating hormone. Using transgenic mice and transfection into a novel gonadotrope lineage cell line, we have identified a regulatory element that confers gonadotrope-specific expression to the glycoprotein hormone alpha-subunit gene. A tissue-specific factor that binds to this element is purified and characterized as a 54-kDa protein which is present uniquely in cells of the gonadotrope lineage and is not Pit-1/GHF-1. The human and equine alpha-subunit genes are also expressed in placental cells. However, the previously characterized placental transcription factors designated TSEB and alpha-ACT are not found in the pituitary gonadotrope cells, indicating that independent mechanisms confer expression of these genes in the two different tissues.

Identification of cis-acting regulatory elements controlling interleukin-4 gene expression in T cells: roles for NF-Y and NF-ATc

1993 ◽  
Vol 13 (8) ◽  
pp. 4793-4805
Author(s):  
S J Szabo ◽  
J S Gold ◽  
T L Murphy ◽  
K M Murphy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Promoter Activity ◽  
Regulatory Elements ◽  
Interleukin 4 ◽  
Specific Factor ◽  
Gene Promoters ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Cis Acting

Activity of the murine interleukin-4 (IL-4) promoter was localized to several cis-acting elements present within the first 300 bp from the transcriptional initiation site. Five repeated elements, P0 to P4, that share the common consensus ATTTTCCNNT were located between -40 and -250, and each was shown to interact with the T-cell-specific factor NF(P). These distinct P sites appear functionally interchangeable and cooperatively confer cyclosporin A-sensitive and ionomycin-inducible promoter activity. NF(P) may be closely related to the cytoplasmic component of NF-AT (nuclear factor of activated T cells), a T-cell-specific factor essential for IL-2 gene transcription, as judged from indistinguishable molecular weights and protease fragmentation patterns of UV-photolabeled factors. Also, we identified an element in the IL-4 promoter with homology to the Y box common to all major histocompatibility complex class II gene promoters. Our data show that the IL-4 promoter Y box -114CTGATTGG-107 significantly enhances overall promoter activity, since point mutations within this element diminish promoter activity by 85%. The factor binding this region is indistinguishable from the cloned nuclear factor NF-Y, as judged from interactions with specific anti-NF-Y monoclonal and polyclonal antibodies. Last, we point out the presence of two sites that share sequence identity to the OAP region of the ARRE-1 site within the IL-2 promoter (K. S. Ullman, W. M. Flanagan, C. A. Edwards, and G. R. Crabtree, Science 254:558-562, 1991). These regions, -85GTGTAATA-78 and -245GTGTAATT-238, reside adjacent to the NF(P) binding sites P1 and P4 and bind a distinct nuclear factor.

scholarly journals T cell receptor beta gene has two downstream DNase I hypersensitive regions. Possible mechanisms of tissue- and stage-specific gene regulation.

1989 ◽  
Vol 169 (6) ◽  
pp. 2097-2107 ◽  
Author(s):  
Y Hashimoto
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lines ◽  
Regulatory Elements ◽  
Dnase I ◽  
The Other ◽  
Specific Gene ◽  
Enhancer Element ◽  
Tissue Specific ◽  
T Cell Lines

Two DNase I-hypersensitive regions were identified downstream of the TCR gene constant region. One of these regions is located at the site of a putative enhancer element and was observed only in T cell lines and not in cell lines derived from other tissues. The other DNase-hypersensitive region was also detected only in T cell lines but only in those expressing TCR-beta RNA. Thus, the first region is probably tissue specific, while the second region is probably tissue and stage specific. The DNA sequence of the second DNase I-hypersensitive region revealed several stretches of nucleotides that are characteristic of consensus sequences for regulatory elements. These results, together with the observations in transgenic mice that indicate a requirement for two distinct regions for optimal TCR gene expression, suggest the presence of at least two regulatory regions downstream of the C-beta-2 region; one is an enhancer region and the other is a transcriptionally related regulatory region. The tissue/stage specificity of these DNase I-hypersensitive regions supports the notion that changes in chromatin structure control tissue-specific gene expression.

scholarly journals INTRODUCTION: Immune Relevant Animal Models: Opportunities and Challenges

ILAR Journal ◽  
2018 ◽  
Vol 59 (3) ◽  
pp. 209-210
Author(s):  
Gregers Jungersen ◽  
Jorge Piedrahita
Keyword(s):  
Immune System ◽  
T Cell ◽  
Animal Models ◽  
Infectious Diseases ◽  
Tissue Specific ◽  
Car T Cell ◽  
Car T ◽  
Preclinical Animal Models

Abstract Valid interpretation of preclinical animal models in immunology-related clinical challenges is important to solve outstanding clinical needs. Given the overall complexity of the immune system and both species- and tissue-specific immune peculiarities, the selection and design of appropriate immune-relevant animal models is, however, not following a straightforward path. The topics in this issue of the ILAR Journal provide assessments of immune-relevant animal models used in oncology, hematopoietic-, CAR-T cell- and xenotransplantation, adjuvants and infectious diseases, and immune privileged inflammation that are providing key insights into unmet human clinical needs.

scholarly journals Genome-wide promoter analysis, homology modeling and protein interaction network of Dehydration Responsive Element Binding (DREB) gene family in Solanum tuberosum

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261215
Author(s):  
Qurat-ul ain-Ali ◽  
Nida Mushtaq ◽  
Rabia Amir ◽  
Alvina Gul ◽  
Muhammad Tahir ◽  
...  
Keyword(s):  
Abiotic Stress ◽  
Gene Family ◽  
Stress Responses ◽  
Promoter Analysis ◽  
Molecular Mechanisms ◽  
Regulatory Elements ◽  
Start Codon ◽  
Gene Promoters ◽  
Responsive Element ◽  
Dreb Gene

Dehydration Responsive Element Binding (DREB) regulates the expression of numerous stress-responsive genes, and hence plays a pivotal role in abiotic stress responses and tolerance in plants. The study aimed to develop a complete overview of the cis-acting regulatory elements (CAREs) present in S. tuberosum DREB gene promoters. A total of one hundred and four (104) cis-regulatory elements (CREs) were identified from 2.5kbp upstream of the start codon (ATG). The in-silico promoter analysis revealed variable sets of cis-elements and functional diversity with the predominance of light-responsive (30%), development-related (20%), abiotic stress-responsive (14%), and hormone-responsive (12%) elements in StDREBs. Among them, two light-responsive elements (Box-4 and G-box) were predicted in 64 and 61 StDREB genes, respectively. Two development-related motifs (AAGAA-motif and as-1) were abundant in StDREB gene promoters. Most of the DREB genes contained one or more Myeloblastosis (MYB) and Myelocytometosis (MYC) elements associated with abiotic stress responses. Hormone-responsive element i.e. ABRE was found in 59 out of 66 StDREB genes, which implied their role in dehydration and salinity stress. Moreover, six proteins were chosen corresponding to A1-A6 StDREB subgroups for secondary structure analysis and three-dimensional protein modeling followed by model validation through PROCHECK server by Ramachandran Plot. The predicted models demonstrated >90% of the residues in the favorable region, which further ensured their reliability. The present study also anticipated pocket binding sites and disordered regions (DRs) to gain insights into the structural flexibility and functional annotation of StDREB proteins. The protein association network determined the interaction of six selected StDREB proteins with potato proteins encoded by other gene families such as MYB and NAC, suggesting their similar functional roles in biological and molecular pathways. Overall, our results provide fundamental information for future functional analysis to understand the precise molecular mechanisms of the DREB gene family in S. tuberosum.

scholarly journals Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Agata Cieslak ◽  
Guillaume Charbonnier ◽  
Melania Tesio ◽  
Eve-Lyne Mathieu ◽  
Mohamed Belhocine ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Regulatory Elements ◽  
T Cell Differentiation ◽  
Epigenetic Changes ◽  
Human T Cell ◽  
Cell Commitment

Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αβ T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.

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