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At least 217 records · Page 12Linked to original sources
PubMed2005

Interplay among coactivator-associated arginine methyltransferase 1, CBP, and CIITA in IFN-gamma-inducible MHC-II gene expression.

Class II major histocompatibility (MHC-II) genes are prototype targets of IFN-gamma. IFN-gamma activates the expression of the non-DNA-binding master regulator of MHC-II, class II transactivator (CIITA), which is crucial for enhanceosome formation and gene activation. This report shows the importance of the histone methyltransferase, coactivator-associated arginine methyltransferase (CARM1/PRMT4), during IFN-gamma-induced MHC-II gene activation. It also demonstrates the coordinated regulation of CIITA, CARM1, and the acetyltransferase cyclic-AMP response element binding (CREB)-binding protein (CBP) during this process. CARM1 synergizes with CIITA in activating MHC-II transcription and synergy is abrogated when an arginine methyltransferase-defective CARM1 mutant is used. Protein-arginine methyltransferase 1 has much less effect on MHC-II transcription. Specific RNA interference reduced CARM1 expression as well as MHC-II expression. The recruitment of CARM1 to the promoter requires endogenous CIITA and results in methylation of histone H3-R17; hence, CIITA is an upstream regulator of histone methylation. Previous work has shown that CARM1 can methylate CBP at three arginine residues. Using wild-type CBP and a mutant of CBP lacking the CARM1-targeted arginine residues (R3A), we show that arginine methylation of CBP is required for IFN-gamma induction of MHC-II. A kinetic analysis shows that CIITA, CARM1, and H3-R17 methylation all precede CBP loading on the MHC-II promoter during IFN-gamma treatment. These results suggest functional and temporal relationships among CIITA, CARM1, and CBP for IFN-gamma induction of MHC-II.

Animals↗
PubMed1999

IFN-gamma regulation of the type IV class II transactivator promoter in astrocytes.

The transcriptional activation of class II MHC genes requires the class II transactivator (CIITA) protein, a regulator that is essential for both constitutive and IFN-gamma-inducible class II MHC expression. The CIITA gene is controlled by multiple independent promoters; two promoters direct constitutive expression, while another, the type IV CIITA promoter, mediates IFN-gamma-induced expression. We investigated the molecular regulation of IFN-gamma-induced type IV CIITA promoter activity in astrocytes. IFN-gamma inducibility of the type IV CIITA promoter is dependent on three cis-acting elements contained within a 154-bp fragment of the promoter; the proximal IFN-gamma activation sequence (GAS) element, the E box, and the proximal IFN regulatory factor (IRF) element. Two IFN-gamma-activated transcription factors, STAT-1alpha and IRF-1, bind the proximal GAS and IRF elements, respectively. The E box binds upstream stimulating factor-1 (USF-1), a constitutively expressed transcription factor. Furthermore, STAT-1alpha binding to the proximal GAS element is dependent on the binding of USF-1 to the adjacent E box. Functionally, the proximal IRF element is essential for IFN-gamma induction of type IV CIITA promoter activity, while the proximal GAS and E box elements contribute to the IFN-gamma inducibility of this promoter. In astrocytes, TNF-alpha enhances IFN-gamma-induced class II MHC transcription. Our results demonstrate that TNF-alpha does not enhance IFN-gamma-induced transcriptional activation of the type IV CIITA promoter, indicating that the enhancing effect of TNF-alpha is mediated downstream of CIITA transcription. These results define the molecular basis of IFN-gamma activation of the type IV CIITA promoter in astrocytes.

Animals↗
PubMed2006

ZXDC, a novel zinc finger protein that binds CIITA and activates MHC gene transcription.

The class II trans-activator (CIITA) is recognized as the master regulator of major histocompatibility complex (MHC) class II gene transcription and contributes to the transcription of MHC class I genes. To better understand the function of CIITA, we performed yeast two-hybrid with the C-terminal 807 amino acids of CIITA, and cloned a novel human cDNA named zinc finger, X-linked, duplicated family member C (ZXDC). The 858 amino acid ZXDC protein contains 10 zinc fingers and a transcriptional activation domain, and was found to interact with the region of CIITA containing leucine-rich repeats. Over-expression of ZXDC in human cell lines resulted in super-activation of MHC class I and class II promoters by CIITA. Conversely, silencing of ZXDC expression reduced the ability of CIITA to activate transcription of MHC class II genes. Given the specific interaction between the ZXDC and CIITA proteins, as well as the effect of ZXDC on MHC gene transcription, it appears that ZXDC is an important regulator of both MHC class I and class II transcription.

Amino Acid Sequence↗
PubMed1993

Antisense oligonucleotides specific for regulatory factor RFX-1 inhibit inducible but not constitutive expression of all major histocompatibility complex class II genes.

The regulation of major histocompatibility complex (MHC) class II genes expression, which can be constitutive, inducible or both, is a crucial aspect of the control of an immune response. It involves binding of various regulatory factors to cis-acting sequences of MHC class II promoters. Antisense oligonucleotides specific for RFX-1, a regulatory factor binding to the functionally essential X box motive of MHC class II promoters, were designed to study the role of RFX-1 in the various modes of MHC class II regulation and explore the possibility of experimentally modulating the level of expression of MHC class II genes by transcriptional intervention. RFX-1 antisense oligonucleotides were first tested in cell-free translation, selected for an inhibitory effect on RFX-1 in vitro translation and then assayed in cell cultures for an effect on human histocompatibility leukocyte antigen (HLA) class II expression. We show that an RFX-1 specific antisense oligonucleotide drastically inhibits induction of HLA-DR,-DQ, and -DP molecules by interferon gamma in monocytic cells. Unexpectedly, the same agent has no effect on the constitutive expression of the same genes either in these cells or in B lymphocytes, indicating an uncoupling of the constitutive and inducible modes of class II regulation. This transient and reversible experimental modulation of MHC class II expression in live cells by transcriptional intervention provides a new tool to study the function of class II molecules in various biological models.

B-Lymphocytes↗
PubMed2000

Identification of class II transcriptional activator-induced genes by representational difference analysis: discoordinate regulation of the DN alpha/DO beta heterodimer.

Class II transcriptional activator (CIITA) is a master regulator of MHC class II genes, including DR, DP, and DQ, and MHC class II-associated genes DM and invariant chain. To determine the repertoire of genes that is regulated by CIITA and to identify uncharacterized CIITA-inducible genes, we used representational difference analysis. Representational difference analysis screens for differentially expressed transcripts. All CIITA-induced genes were MHC class II related. We have identified the alpha subunit, DN alpha, of the class II processing factor DO as an additional CIITA-inducible gene. Northern analysis confirmed that DN alpha is induced by IFN-gamma in 2fTGH fibrosarcoma cells, and CIITA is necessary for high-level expression in B cells. The beta subunit, DO beta, is not inducible in fibrosarcoma cells by IFN-gamma or exogenous CIITA expression. Moreover, in contrast to other class II genes, DO beta expression remains high in the absence of CIITA in B cells. The promoters for DN alpha and DO beta contain the highly conserved WXY motifs, and, like other class II genes, expression of both DN alpha and DO beta requires RFX. These findings demonstrate that both DN alpha and DO beta are regulated by RFX. However, DN alpha is defined for the first time as a CIITA-inducible gene, and DO beta as a MHC class II gene whose expression is independent of CIITA.

Amino Acid Sequence↗
PubMed1998

Regulation of MHC class I and II gene transcription: differences and similarities.

Major histocompatibility complex (MHC) molecules serve as peptide receptors. These peptides are derived from processed cellular or extra-cellular antigens. The MHC gene complex encodes two major classes of molecules, MHC class I and class II, whose function is to present peptides to CD8+ (cytotoxic) and CD4+ (helper) T cells, respectively. The genes encoding both classes of MHC molecules seem to originate from a common ancestral gene. One of the hallmarks of the MHC is its extensive polymorphism which displays locus and allele-specific characteristics among the various MHC class I and class II genes. Because of its central role in immunosurveillance and in various disease states, the MHC is one of the best studied genetic systems. This review addresses several aspects of MHC class I and class II gene regulation in human and in particular, the contribution to the constitutive and cytokine-induced expression of MHC class I and II genes of MHC class-specific regulatory elements and regulatory elements which apparently are shared by the promoters of MHC class I and class II genes.

Animals↗
PubMed1997

Neonatal lupus erythematosus: HLA-DR and -DQ distributions are different among the groups of anti-Ro/SSA-positive mothers with different neonatal outcomes.

Neonatal lupus erythematosus (NLE) is an antibody-mediated disorder of infants characterized by two major clinical manifestations; cutaneous lupus lesions and congenital heart block (CHB). The disease is associated with placentally transferred maternal anti-Ro/SSA and/or La/SSB antibodies. There is a tendency for the same disease expression to occur within a sibship. To reveal a possible association of class II MHC genes with maternal anti-Ro/SSA autoimmune responses and neonatal outcomes in NLE with a relatively homogeneous ethnic background, haplotype, and allele distributions were analyzed based on the PCR-RFLP results in 26 Japanese anti-Ro/SSA-positive mothers from three groups defined by neonatal outcomes. The results were as follows: (i) maternal HLA-DR5 haplotype DRB1*1101-DQA1*0501-DQB1*0301 and individual class II alleles making up this haplotype were significantly associated with neonatal cutaneous lupus but not CHB. Conversely, maternal HLA-DQB1*0602 carried on HLA-DR2 haplotypes was associated with CHB but not cutaneous NLE; (ii) HLA-DQA1 alleles with glutamine at position 34 of the first domain, which have reportedly been associated with the autoimmune responses to Ro/SSA antigens in other ethnic groups, were increased in the mothers of infants with cutaneous involvement; and (iii) there was no particular class II HLA profile that distinguished the disease manifestations in infants. These findings suggest that specific maternal MHC class II genes might correlate with specific neonatal outcomes in NLE.

Adult↗
PubMed1990

Restriction fragment polymorphism of the cynomolgus monkey major histocompatibility complex.

Among old world monkeys, the major histocompatibility complex (MHC) is defined only in the rhesus (Macaca mulatta), cynomolgus (Macaca fascicularis) and pigtailed (Macaca nemistrina) species. However, little is known about the organization of class I and class II MHC genes or the extent of polymorphism in macaques. In the present study, human and murine class I and class II gene probes were used to analyze the leukocyte antigen (CyLA) system of unrelated and related cynomolgus monkeys. Restriction fragment length polymorphism (RFLP) analysis with a HLA-B7 cDNA probe supports the serologic evidence indicating the existence of a family of class I loci of which several are highly polymorphic. As in the human MHC, the class II beta genes are more polymorphic than class II alpha genes. In a pedigree study, RFLP patterns correlated with CyLA haplotypes as deduced from CyLA-A,B,C and complement factor B(Bf) phenotypes. The RFLP data are consistent with three expressed class I gene loci as well as nonclassical MHC genes potentially related to Qa/T1a in mice. We conclude that the RFLP analysis with cross-hybridizing DNA probes augments the information obtained by serotyping and sets the stage for gene mapping and structural analysis of the CyLA region.

Animals↗
PubMed1987

The HLA-DQ beta gene upstream region contains an immunoglobulin-like octamer motif that binds cell-type specific nuclear factors.

A method is described for scanning relatively large fragments of DNA for sequences which bind nuclear factors. This method was used to identify an octamer (ATTTGTAT) in the DQ beta gene upstream region which differs from the immunoglobulin gene octamer (ATTTGCAT) by only 1 bp. The DQ beta gene octamer binds two proteins, one (B2) appears to be B cell specific while the other (B1) is not. These factors are either similar or identical to factors which bind to the octamer motif in immunoglobulin genes. All other class II MHC genes for which sequence information is available contain an octamer motif in their upstream region. Thus, the possibility that these sequences regulate B cell specific expression of class II MHC genes requires careful evaluation.

Base Sequence↗
PubMed1994

Developmental extinction of major histocompatibility complex class II gene expression in plasmocytes is mediated by silencing of the transactivator gene CIITA.

Constitutive major histocompatibility complex (MHC) class II gene expression is tightly restricted to antigen presenting cells and is under developmental control. Cells of the B cell lineage acquire the capacity to express MHC class II genes early during ontogeny and lose this property during terminal differentiation into plasma cells. Cell fusion experiments have suggested that the extinction of MHC class II expression in plasma cells is due to a dominant repression, but the underlying mechanisms are not understood. CIITA was recently identified as an MHC class II transactivator that is essential for MHC class II expression in B lymphocytes. We show here that inactivation of MHC class II genes in plasmocytes is associated with silencing of the CIITA gene. Moreover, experimentally induced expression of CIITA in plasmocytes leads to reexpression of MHC class II molecules to the same level as that observed on B lymphocytes. We therefore conclude that the loss of MHC class II expression observed upon terminal differentiation of B lymphocytes into plasmocytes results from silencing of the transactivator gene CIITA.

B-Lymphocytes↗
PubMed1998

Genomics and polymorphism of Agph-DAB1, an Mhc class II B gene in red-winged blackbirds (Agelaius phoeniceus).

To further our understanding of the evolution of avian Mhc genes at the genomic level, we screened a cosmid library made from a red-winged blackbird (Agelaius phoeniceus) with a blackbird cDNA probe and subcloned from one of the Mhc-containing cosmids a gene which we designate Agph-DAB1. The structure of the gene is similar to that found for chicken class II B genes, except that the introns are surprisingly large, ranging from 98 to over 600 bp, making this the longest avian class II B gene to date. Using primers targeted toward the introns flanking the peptide-binding region (PBR), we amplified the entirety of the second exon and determined nucleotide sequences of 41 PCR products from eight individual blackbirds. The 10 sequence types found, among which were two probable pseudogene sequences, exhibit the classic hallmarks for evolution of PBRs, namely, an excess of nonsynonymous over synonymous substitutions and evidence of gene conversion events in polymorphic subdomains. Despite these patterns and our use of intron primers, the distribution of sequences among individuals suggests that more than one locus was amplified in most individuals, and the bushlike tree of sequences provides little information as to locus-specific clusters. These results imply a complex history of gene conversion, recent duplication, or possibly, concerted evolution among multiple loci, although Agph-DAB1, the first genomic Mhc sequence from a bird other than chicken, provides important clues in the quest for locus-specific Mhc primers in birds.

Amino Acid Sequence↗
PubMed2000

Mhc class II B gene evolution in East African cichlid fishes.

A distinctive feature of essential major histocompatibility complex (Mhc) loci is their polymorphism characterized by large genetic distances between alleles and long persistence times of allelic lineages. Since the lineages often span several successive speciations, we investigated the behavior of the Mhc alleles during or close to the speciation phase. We sequenced exon 2 of the class II B locus 4 from 232 East African cichlid fishes representing 32 related species. The divergence times of the (sub)species ranged from 6,000 to 8.4 million years. Two types of evolutionary analysis were used to elucidate the pattern of exon 2 sequence divergence. First, phylogenetic methods were applied to reconstruct the most likely evolutionary pathways leading from the last common ancestor of the set to the extant sequences, and to assess the probable mechanisms involved in allelic diversification. Second, pairwise comparisons of sequences were carried out to detect differences seemingly incompatible with origin by nonparallel point mutations. The analysis revealed point mutations to be the most important mechanism behind allelic divergences, with recombination playing only an auxiliary part. Comparison of sequences from related species revealed evidence of random allelic (lineage) losses apparently associated with speciation. Sharing of identical alleles could be demonstrated between species that diverged 2 million years ago. The phylogeny of the exon was incongruent with that of the flanking introns, indicating either a high degree of convergent evolution at the peptide-binding region-encoding sites, or intron homogenization.

Amino Acid Sequence↗
PubMed1991

Repression of class II major histocompatibility complex genes by cyclic AMP is mediated by conserved promoter elements.

The induction of cell surface expression of class II major histocompatibility complex (MHC) antigens by interleukin (IL)-4 and interferon (IFN)-gamma is inhibited by elevation of intracellular cyclic (c)AMP, which is caused by immunomodulatory agents such as E series prostaglandins (PGEs). To investigate the mechanism of this downregulation, we have analyzed the consequences of elevating intracellular cAMP on cell surface expression, mRNA levels, and promoter activity of the murine A alpha and E beta class II MHC genes. Elevation of cAMP resulted in a coordinate repression of both basal and inducible A alpha and E beta expression. 151 and 192 base pairs of A alpha and E beta promoter sequence, respectively, were sufficient for conferring repression by cAMP on a reporter gene. A mutational analysis of the A alpha promoter revealed that cAMP downregulation is mediated by the conserved S and X1 DNA elements, which are also necessary for induction by cytokines. Downregulation by cAMP was not dependent on an intact X2 site, which is identical in sequence to the CRE element which mediates the positive regulation of several genes by cAMP. These results identify the DNA elements which mediate repression of class II MHC genes by cAMP and show that the same DNA sequences can mediate both positive and negative regulation of class II MHC expression.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1989

The class II genes of the rat MHC.

Genes that encode class II Ag from the MHC of the rat, the RT1 region, have been isolated as a series of cosmid clones. The cosmids define two clusters, each of which contains three identifiable sequences; one homologous to alpha-chain and two to beta-chain genes. Both the serologically identified rat class II Ag have been expressed in mouse L cell fibroblasts after the introduction of each alpha-chain gene along with a beta-chain gene from the same cluster. There are substantial homologies to the I region of the mouse H-2 complex in the presence, location, orientation, and expression of the six identified sequences from the rat RT1, supporting the view that the overall organization of the two gene complexes has remained conserved since the species separated.

Animals↗
PubMed1993

Major histocompatibility complex genes have an increased brain expression after scrapie infection.

We have examined the expression of the major histocompatibility complex (MHC) antigens and related genes in scrapie-infected hamster brain. Both the class I and the class II MHC genes as well as the class II-associated invariant chain were found to have an increased brain expression after scrapie infection. The increased expression of the class I complex was immunohistochemically localized primarily to neurons, though some astrocytes contained much smaller amounts of the class I complex. While there is no detectable immune response to scrapie infection, the possibility that increased MHC expression affords some defense against the scrapie agent is discussed.

Animals↗
PubMed1987

Regulation of the expression of class II genes of the human major histocompatibility complex in tumor cells.

The control of expression of human class II MHC genes has been studied in lymphoid and melanoma cells. Specific unmethylation of all restriction sites nearby the promoter regions has been detected in all cell lines and tissues studied, irrespective of their ability to express class II MHC products. The main functional role of DNA methylation appears, on the contrary, to be the regulation of a fraction of the nucleotide polymorphism of class II MHC genes. Constitutive expression of these genes can be modified by recombinant IFN-gamma and by the demethylating agent 5-azacytidine. Both the modifiers differentially regulate the levels of class II MHC and invariant chain products. In melanoma cells IFN-gamma derepresses transcription of a 1.2-Kb HLA-DR alpha mRNA, but does not affect the levels of a 0.8-Kb HLA-DR alpha specific mRNA. These molecular changes are triggered by IFN-gamma through a protein-synthesis-dependent pathway.

Azacitidine↗
PubMed2002

Murine NFX.1: isolation and characterization of its messenger RNA, mapping of its chromosomal location and assessment of its developmental expression.

We have previously isolated (by expression cloning) a human cDNA, termed NFX.1, encoding a nucleic acid-binding protein that interacts with the conserved X1 box cis-element first discovered in class II major histocompatibility complex (MHC) genes. Functional studies involving expression of NFX.1 and assessment of expression from class II reporter constructs and endogenous class II MHC genes indicated that the factor could repress transcription of class II MHC genes. Subsequent studies have extended the biological significance of the factor, indicating that it plays an important role in neuronal development. Indeed, the reiterated RING finger motifs in the central domain of the polypeptide strongly suggest that NF-XI is a probable E3 ubiquitin protein ligase, indicating that the protein may have multiple activities. Here we report the cloning of the mouse homologue of the human NfX.1 cDNA: m-Nfx.1. Comparison of the deduced primary sequence of mouse and human NFX.1 proteins shows very high homology and confirms that m-NFX.1 contains the conserved cysteine-rich DNA-binding motif first described in human NFX.1 (95% homology). Expression of MHC class II genes is substantially reduced following expression of m-NFX.1, which confirms that we have isolated the functional murine homologue of human NfX.1 cDNA. Further evidence comes from the mapping of m-Nfx.1 gene to the proximal region of mouse chromosome 4, a region syntenic to the location of human Nfx.1 (short arm of chromosome 9). Expression profiling shows that m-NFX.1 is expressed ubiquitously in both adult tissues and during development, supporting the hypothesis that it may have yet-undescribed roles in distinct biological processes.

Aging↗