scholarly journals The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions

2008 ◽  
Vol 205 (4) ◽  
pp. 785-798 ◽  
Author(s):  
Parimal Majumder ◽  
Jorge A. Gomez ◽  
Brian P. Chadwick ◽  
Jeremy M. Boss
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Proximal Promoter ◽  
Factor X ◽  
Promoter Regions ◽  
Long Distance ◽  
Mhc Ii ◽  
Hla Dqa1 ◽  
In Situ Hybridizations

Knockdown of the insulator factor CCCTC binding factor (CTCF), which binds XL9, an intergenic element located between HLA-DRB1 and HLA-DQA1, was found to diminish expression of these genes. The mechanism involved interactions between CTCF and class II transactivator (CIITA), the master regulator of major histocompatibility complex class II (MHC-II) gene expression, and the formation of long-distance chromatin loops between XL9 and the proximal promoter regions of these MHC-II genes. The interactions were inducible and dependent on the activity of CIITA, regulatory factor X, and CTCF. RNA fluorescence in situ hybridizations show that both genes can be expressed simultaneously from the same chromosome. Collectively, the results suggest a model whereby both HLA-DRB1 and HLA-DQA1 loci can interact simultaneously with XL9, and describe a new regulatory mechanism for these MHC-II genes involving the alteration of the general chromatin conformation of the region and their regulation by CTCF.

scholarly journals A super enhancer controls expression and chromatin architecture within the MHC class II locus

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Parimal Majumder ◽  
Joshua T. Lee ◽  
Andrew R. Rahmberg ◽  
Gaurav Kumar ◽  
Tian Mi ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Three Dimensional ◽  
Class Ii ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Mhc Ii ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Cell Type Specific ◽  
Hla Dqa1

Super enhancers (SEs) play critical roles in cell type–specific gene regulation. The mechanisms by which such elements work are largely unknown. Two SEs termed DR/DQ-SE and XL9-SE are situated within the human MHC class II locus between the HLA-DRB1 and HLA-DQA1 genes and are highly enriched for disease-causing SNPs. To test the function of these elements, we used CRISPR/Cas9 to generate a series of mutants that deleted the SE. Deletion of DR/DQ-SE resulted in reduced expression of HLA-DRB1 and HLA-DQA1 genes. The SEs were found to interact with each other and the promoters of HLA-DRB1 and HLA-DQA1. DR/DQ-SE also interacted with neighboring CTCF binding sites. Importantly, deletion of DR/DQ-SE reduced the local chromatin interactions, implying that it functions as the organizer for the local three-dimensional architecture. These data provide direct mechanisms by which an MHC-II SE contributes to expression of the locus and suggest how variation in these SEs may contribute to human disease and altered immunity.

scholarly journals Long Distance Control of MHC Class II Expression by Multiple Distal Enhancers Regulated by Regulatory Factor X Complex and CIITA

2004 ◽  
Vol 173 (10) ◽  
pp. 6200-6210 ◽  
Author(s):  
Michal Krawczyk ◽  
Nicolas Peyraud ◽  
Natalia Rybtsova ◽  
Krzysztof Masternak ◽  
Philipp Bucher ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Class Ii ◽  
Factor X ◽  
Regulatory Factor ◽  
Long Distance ◽  
Distance Control

scholarly journals The MHC Class II Transactivator CIITA: Not (Quite) the Odd-One-Out Anymore among NLR Proteins

2021 ◽  
Vol 22 (3) ◽  
pp. 1074
Author(s):  
Jorge Alfonso León Machado ◽  
Viktor Steimle
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Protein Interactions ◽  
Transcriptional Regulator ◽  
Class Ii ◽  
Class Ii Transactivator ◽  
Mhc I ◽  
Mhc Ii ◽  
Mhc Class Ii Transactivator

In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein–protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Inhibits Major Histocompatibility Complex Class II Expression by Disrupting Enhanceosome Assembly through Binding with the Regulatory Factor X Complex

2015 ◽  
Vol 89 (10) ◽  
pp. 5536-5556 ◽  
Author(s):  
Suhani Thakker ◽  
Pravinkumar Purushothaman ◽  
Namrata Gupta ◽  
Shanthan Challa ◽  
Qiliang Cai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Class Ii ◽  
Nuclear Antigen ◽  
Factor X ◽  
Mhc Ii ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Rfx Complex ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACTMajor histocompatibility complex class II (MHC-II) molecules play a central role in adaptive antiviral immunity by presenting viral peptides to CD4+T cells. Due to their key role in adaptive immunity, many viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), have evolved multiple strategies to inhibit the MHC-II antigen presentation pathway. The expression of MHC-II, which is controlled mainly at the level of transcription, is strictly dependent upon the binding of the class II transactivator (CIITA) to the highly conserved promoters of all MHC-II genes. The recruitment of CIITA to MHC-II promoters requires its direct interactions with a preassembled MHC-II enhanceosome consisting of cyclic AMP response element-binding protein (CREB) and nuclear factor Y (NF-Y) complex and regulatory factor X (RFX) complex proteins. Here, we show that KSHV-encoded latency-associated nuclear antigen (LANA) disrupts the association of CIITA with the MHC-II enhanceosome by binding to the components of the RFX complex. Our data show that LANA is capable of binding to all three components of the RFX complex, RFX-associated protein (RFXAP), RFX5, and RFX-associated ankyrin-containing protein (RFXANK),in vivobut binds more strongly with the RFXAP component inin vitrobinding assays. Levels of MHC-II proteins were significantly reduced in KSHV-infected as well as LANA-expressing B cells. Additionally, the expression of LANA in a luciferase promoter reporter assay showed reduced HLA-DRA promoter activity in a dose-dependent manner. Chromatin immunoprecipitation assays showed that LANA binds to the MHC-II promoter along with RFX proteins and that the overexpression of LANA disrupts the association of CIITA with the MHC-II promoter. These assays led to the conclusion that the interaction of LANA with RFX proteins interferes with the recruitment of CIITA to MHC-II promoters, resulting in an inhibition of MHC-II gene expression. Thus, the data presented here identify a novel mechanism used by KSHV to downregulate the expressions of MHC-II genes.IMPORTANCEKaposi's sarcoma-associated herpesvirus is the causative agent of multiple human malignancies. It establishes a lifelong latent infection and persists in infected cells without being detected by the host's immune surveillance system. Only a limited number of viral proteins are expressed during latency, and these proteins play a significant role in suppressing both the innate and adaptive immunities of the host. Latency-associated nuclear antigen (LANA) is one of the major proteins expressed during latent infection. Here, we show that LANA blocks MHC-II gene expression to subvert the host immune system by disrupting the MHC-II enhanceosome through binding with RFX transcription factors. Therefore, this study identifies a novel mechanism utilized by KSHV LANA to deregulate MHC-II gene expression, which is critical for CD4+T cell responses in order to escape host immune surveillance.

scholarly journals The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions

2008 ◽  
Vol 180 (6) ◽  
pp. i19-i19
Author(s):  
Parimal Majumder ◽  
Jorge A. Gomez ◽  
Brian P. Chadwick ◽  
Jeremy M. Boss
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Long Distance ◽  
Chromatin Interactions

scholarly journals Synaptic Clusters of MHC Class II Molecules Induced on DCs by Adhesion Molecule–mediated Initial T-Cell Scanning

2005 ◽  
Vol 16 (7) ◽  
pp. 3314-3322 ◽  
Author(s):  
Hortensia de la Fuente ◽  
María Mittelbrunn ◽  
Lorena Sánchez-Martín ◽  
Miguel Vicente-Manzanares ◽  
Amalia Lamana ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Regulatory Pathway ◽  
Immune Synapse ◽  
Mhc Ii ◽  
Cytoskeleton Reorganization ◽  
Adhesive Contacts ◽  
Enhance Antigen Presentation ◽  
Mhc Class Ii Molecules

Initial adhesive contacts between T lymphocytes and dendritic cells (DCs) facilitate recognition of peptide-MHC complexes by the TCR. In this report, we studied the dynamic behavior of adhesion and Ag receptors on DCs during initial contacts with T-cells. Adhesion molecules LFA-1- and ICAM-1,3-GFP as well as MHC class II-GFP molecules were very rapidly concentrated at the DC contact area. Binding of ICAM-3, and ICAM-1 to a lesser extent, to LFA-1 expressed by mature but not immature DC, induced MHC-II clustering into the immune synapse. Also, ICAM-3 binding to DC induced the activation of the Vav1-Rac1 axis, a regulatory pathway involved in actin cytoskeleton reorganization, which was essential for MHC-II clustering on DCs. Our results support a model in which ICAM-mediated MHC-II clustering on DC constitutes a priming mechanism to enhance antigen presentation to T-cells.

scholarly journals Major Histocompatibility Complex Class II+ Invariant Chain Negative Breast Cancer Cells Present Unique Peptides that Activate Tumor-specific T Cells from Breast Cancer Patients

2012 ◽  
Vol 11 (11) ◽  
pp. 1457-1467 ◽  
Author(s):  
Olesya Chornoguz ◽  
Alexei Gapeev ◽  
Michael C. O'Neill ◽  
Suzanne Ostrand-Rosenberg
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Mhc Class Ii ◽  
Breast Cancer Cells ◽  
Class Ii ◽  
Breast Cancer Patients ◽  
Mhc Ii ◽  
Peptide Loading

The major histocompatibility complex (MHC) class II-associated Invariant chain (Ii) is present in professional antigen presenting cells where it regulates peptide loading onto MHC class II molecules and the peptidome presented to CD4+ T lymphocytes. Because Ii prevents peptide loading in neutral subcellular compartments, we reasoned that Ii− cells may present peptides not presented by Ii+ cells. Based on the hypothesis that patients are tolerant to MHC II-restricted tumor peptides presented by Ii+ cells, but will not be tolerant to novel peptides presented by Ii− cells, we generated MHC II vaccines to activate cancer patients' T cells. The vaccines are Ii− tumor cells expressing syngeneic HLA-DR and the costimulatory molecule CD80. We used liquid chromatography coupled with mass spectrometry to sequence MHC II-restricted peptides from Ii+ and Ii− MCF10 human breast cancer cells transfected with HLA-DR7 or the MHC Class II transactivator CIITA to determine if Ii− cells present novel peptides. Ii expression was induced in the HLA-DR7 transfectants by transfection of Ii, and inhibited in the CIITA transfectants by RNA interference. Peptides were analyzed and binding affinity predicted by artificial neural net analysis. HLA-DR7-restricted peptides from Ii− and Ii+ cells do not differ in size or in subcellular location of their source proteins; however, a subset of HLA-DR7-restricted peptides of Ii− cells are not presented by Ii+ cells, and are derived from source proteins not used by Ii+ cells. Peptides from Ii− cells with the highest predicted HLA-DR7 binding affinity were synthesized, and activated tumor-specific HLA-DR7+ human T cells from healthy donors and breast cancer patients, demonstrating that the MS-identified peptides are bonafide tumor antigens. These results demonstrate that Ii regulates the repertoire of tumor peptides presented by MHC class II+ breast cancer cells and identify novel immunogenic MHC II-restricted peptides that are potential therapeutic reagents for cancer patients.

Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X

Cell ◽  
1988 ◽  
Vol 53 (6) ◽  
pp. 897-906 ◽  
Author(s):  
W. Reith ◽  
S. Satola ◽  
C. Herrero Sanchez ◽  
I. Amaldi ◽  
B. Lisowska-Grospierre ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Binding Protein ◽  
Class Ii ◽  
Hla Dr ◽  
Congenital Immunodeficiency ◽  
Regulatory Defect

scholarly journals MPYS, a Novel Membrane Tetraspanner, Is Associated with Major Histocompatibility Complex Class II and Mediates Transduction of Apoptotic Signals

2008 ◽  
Vol 28 (16) ◽  
pp. 5014-5026 ◽  
Author(s):  
Lei Jin ◽  
Paul M. Waterman ◽  
Karen R. Jonscher ◽  
Cindy M. Short ◽  
Nichole A. Reisdorph ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cell Activation ◽  
Cytoplasmic Tail ◽  
Class Ii ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Death Signals

ABSTRACT Although the best-defined function of type II major histocompatibility complex (MHC-II) is presentation of antigenic peptides to T lymphocytes, these molecules can also transduce signals leading alternatively to cell activation or apoptotic death. MHC-II is a heterodimer of two transmembrane proteins, each containing a short cytoplasmic tail that is dispensable for transduction of death signals. This suggests the function of an undefined MHC-II-associated transducer in signaling the death response. Here we describe a novel plasma membrane tetraspanner (MPYS) that is associated with MHC-II and mediates its transduction of death signals. MPYS is unusual among tetraspanners in containing an extended C-terminal cytoplasmic tail (∼140 amino acids) with multiple embedded signaling motifs. MPYS is tyrosine phosphorylated upon MHC-II aggregation and associates with inositol lipid and tyrosine phosphatases. Finally, MHC class II-mediated cell death signaling requires MPYS-dependent activation of the extracellular signal-regulated kinase signaling pathway.

scholarly journals Cross-linking of major histocompatibility complex class II molecules by staphylococcal enterotoxin A superantigen is a requirement for inflammatory cytokine gene expression.

1995 ◽  
Vol 182 (5) ◽  
pp. 1573-1577 ◽  
Author(s):  
K Mehindate ◽  
J Thibodeau ◽  
M Dohlsten ◽  
T Kalland ◽  
R P Sékaly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Messenger Rna ◽  
Class Ii ◽  
Cytokine Gene Expression ◽  
Cross Linking ◽  
Staphylococcal Enterotoxin A ◽  
Cytokine Gene ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Molecules

Staphylococcal enterotoxin A (SEA) has two distinct binding sites for major histocompatibility complex (MHC) class II molecules. The aspartic acid located at position 227 (D227) in the COOH terminus of SEA is one of the three residues involved in its interaction with the DR beta chain, whereas the phenylalanine 47 (F47) of the NH2 terminus is critical for its binding to the DR alpha chain. Upon interaction with MHC class II molecules, SEA triggers several cellular events leading to cytokine gene expression. In the present study, we have demonstrated that, contrary to wild-type SEA, stimulation of the THP1 monocytic cell line with SEA mutated at position 47 (SEAF47A) or at position 227 (SEAD227A) failed to induce interleukin 1 beta and tumor necrosis factor-alpha messenger RNA expression. Pretreatment of the cells with a 10-fold excess of either SEAF47A or SEAD227A prevented the increase in cytokine messenger RNA induced by wild-type SEA. However, cross-linking of SEAF47A or SEAD227A bound to MHC class II molecules with F(ab')2 anti-SEA mAb leads to cytokine gene expression, whereas cross-linking with F(ab) fragments had no effect. Taken together, these results indicate that cross-linking of two MHC class II molecules by one single SEA molecule is a requirement for cytokine gene expression.

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