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 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.

The Murine MHC Class II Super Enhancer IA/IE-SE Contains a Functionally Redundant CTCF-Binding Component and a Novel Element Critical for Maximal Expression

2021 ◽  
pp. ji2001089
Author(s):  
Parimal Majumder ◽  
Joshua T. Lee ◽  
Benjamin G. Barwick ◽  
Dillon G. Patterson ◽  
Alexander P. R. Bally ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Class Ii ◽  
Ctcf Binding ◽  
Super Enhancer ◽  
Maximal Expression ◽  
Binding Component

scholarly journals Deeply hidden genome organization directly mediated by SATB1

2021 ◽  
Author(s):  
Yoshinori Kohwi ◽  
Mari Grange ◽  
Hunter W Richards ◽  
Ya-Chen Liang ◽  
Cheng-Ming Chuong ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Genome Architecture ◽  
Cell Type ◽  
Topologically Associated Domains ◽  
Chromatin Folding ◽  
Cell Type Specific ◽  
Cellular Phenotypes

Mammalian genomes are organized by multi-layered chromatin folding. Whether and how three-dimensional genome organization contributes to cell-type specific transcription remains unclear. Here we uncover genome architecture formed by specialized sequences, base-unpairing regions (BURs), bound to a nuclear architectural protein, SATB1. SATB1 regulates cell-type specific transcription that underlies changes in cellular phenotypes. We developed a modified ChIP-seq protocol that stringently purifies genomic DNA only with its directly-associated proteins and unmasked previously-hidden BURs as direct SATB1 targets genome-wide. These SATB1-bound BURs are mutually exclusive from CTCF binding sites, and SATB1 is dispensable for CTCF/cohesion-mediated topologically associated domains (TADs). Instead, BURs largely overlap with lamina associated domains (LADs), and the fraction of BURs tethered to the SATB1 protein network in the nuclear interior is cell type-dependent. Our results reveal TAD-independent chromatin folding mediated by BUR sequences, which serve as genome architecture landmarks targeted by SATB1, to regulate cell-type specific gene expression.

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.

scholarly journals HiCRes: a computational method to estimate and predict the resolution of HiC libraries

2020 ◽  
Author(s):  
Claire Marchal ◽  
Nivedita Singh ◽  
Ximena Corso-Díaz ◽  
Anand Swaroop
Keyword(s):  
Expression Patterns ◽  
Three Dimensional ◽  
Computational Method ◽  
Mathematical Concepts ◽  
Regulate Gene Expression ◽  
Chromatin Interactions ◽  
Genome Wide ◽  
A Cell ◽  
Cell Type Specific ◽  
Human And Mouse

AbstractThree-dimensional (3D) conformation of the chromatin is crucial to stringently regulate gene expression patterns and DNA replication in a cell-type specific manner. HiC is a key technique for measuring 3D chromatin interactions genome wide. Estimating and predicting the resolution of a library is an essential step in any HiC experimental design. Here, we present the mathematical concepts to estimate the resolution of a library and predict whether deeper sequencing would enhance the resolution. We have developed HiCRes, a docker pipeline, by applying these concepts to human and mouse HiC libraries.

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 In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes

2000 ◽  
Vol 191 (1) ◽  
pp. 97-104 ◽  
Author(s):  
Li Wen ◽  
F. Susan Wong ◽  
Jie Tang ◽  
Ning-Yuan Chen ◽  
Martha Altieri ◽  
...  
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Mhc Class Ii ◽  
Spontaneous Diabetes ◽  
Class Ii ◽  
Β Cells ◽  
Leukocyte Antigen ◽  
Hla Dqa1 ◽  
Mhc Class Ii Molecules

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8+/mII−). They did not develop insulitis or spontaneous diabetes. However, when DQ8+/mII− mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on β cells (which normally do not develop diabetes), 81% of the DQ8+/mII−/B7-1+ mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4+ and CD8+) and B cells. T cells from the diabetic mice secreted large amounts of interferon γ, but not interleukin 4, in response to DQ8+ islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8+/mII−/B7-1+ mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic β cells (DQ6+/mII−/B7-1+) developed diabetes. Only 7% of DQ−/mII−/B7-1+ mice developed diabetes at an older age, and none of the DQ−/mII+/B7-1+ mice or DQ8+/mII+/B7-1+ mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non–diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique “humanized” animal model of spontaneous diabetes.

The role of CTCF in coordinating the expression of single gene loci

2011 ◽  
Vol 89 (5) ◽  
pp. 489-494 ◽  
Author(s):  
Austin E Gillen ◽  
Ann Harris
Keyword(s):  
Gene Expression ◽  
Mhc Class Ii ◽  
Noncoding Rna ◽  
Single Gene ◽  
Functional Model ◽  
Gene Clusters ◽  
Ctcf Binding ◽  
Chromatin Interactions ◽  
Insulator Elements

The CCCTC-binding factor (CTCF), which binds insulator elements in vertebrates, also facilitates coordinated gene expression at several gene clusters, including the β-globin, Igf2/H19 (insulin like growth factor 2/H19 noncoding RNA), and major histocompatibility complex (MHC) class II loci. CTCF controls expression of these genes both by enabling insulator function and facilitating higher order chromatin interactions. While the role of CTCF in gene regulation is best studied at these multi-gene loci, there is also evidence that CTCF contributes to the regulated expression of single genes. Here, we discuss how CTCF participates in coordinating gene expression at the CFTR (cystic fibrosis transmembrane conductance regulator) and IFNG (interferon-gamma) loci. We consider the structural similarities between the loci with regard to CTCF-binding elements, the possible interaction between nuclear receptors and CTCF, and the role of CTCF in chromatin looping at these genes. These comparisons reveal a functional model that may be applicable to other single-gene loci that require CTCF for coordinated gene expression.

scholarly journals Susceptibility of amphibians to chytridiomycosis is associated with MHC class II conformation

2015 ◽  
Vol 282 (1805) ◽  
pp. 20143127 ◽  
Author(s):  
Arnaud Bataille ◽  
Scott D. Cashins ◽  
Laura Grogan ◽  
Lee F. Skerratt ◽  
David Hunter ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Batrachochytrium Dendrobatidis ◽  
Binding Pocket ◽  
Class Ii ◽  
Population Declines ◽  
Mhc Ii ◽  
Resistant Species ◽  
Binding Pockets ◽  
Experimental Approaches ◽  
Binding Groove

The pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) can cause precipitous population declines in its amphibian hosts. Responses of individuals to infection vary greatly with the capacity of their immune system to respond to the pathogen. We used a combination of comparative and experimental approaches to identify major histocompatibility complex class II (MHC-II) alleles encoding molecules that foster the survival of Bd-infected amphibians. We found that Bd-resistant amphibians across four continents share common amino acids in three binding pockets of the MHC-II antigen-binding groove. Moreover, strong signals of selection acting on these specific sites were evident among all species co-existing with the pathogen. In the laboratory, we experimentally inoculated Australian tree frogs with Bd to test how each binding pocket conformation influences disease resistance. Only the conformation of MHC-II pocket 9 of surviving subjects matched those of Bd-resistant species. This MHC-II conformation thus may determine amphibian resistance to Bd, although other MHC-II binding pockets also may contribute to resistance. Rescuing amphibian biodiversity will depend on our understanding of amphibian immune defence mechanisms against Bd. The identification of adaptive genetic markers for Bd resistance represents an important step forward towards that goal.

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