X Box-Like Sequences in the MHC Class II Region Maintain Regulatory Function

Gómez, Jorge; Majumder, Parimal; Nagarajan, Uma M.; Boss, Jeremy M.

doi:10.4049/jimmunol.175.2.1030

Cited by 46 publications

(64 citation statements)

References 44 publications

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“…Indeed, DNA looping and interactions of distal enhancers and locus control regions with promoters are important for the expression of MHC class II and ␤-globin genes (12,42), which are regulated at the level of transcriptional elongation. Moreover, one study found AIRE to be associated with such matrix attachment sites (44).…”

Section: Discussionmentioning

confidence: 99%

AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells

Oven

Brdičková

Kohoutek

et al. 2007

Molecular and Cellular Biology

142

131

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AIRE is a transcriptional activator that directs the ectopic expression of many tissue-specific genes in medullary thymic epithelial cells, which plays an important role in the negative selection of autoreactive T cells. However, its mechanism of action remains poorly understood. In this study, we found that AIRE regulates the step of elongation rather than initiation of RNA polymerase II. For these effects, AIRE bound and recruited P-TEFb to target promoters in medullary thymic epithelial cells. In these cells, AIRE activated the ectopic transcription of insulin and salivary protein 1 genes. Indeed, by chromatin immunoprecipitation, we found that RNA polymerase II was already engaged on these promoters but was unable to elongate in the absence of AIRE. Moreover, the genetic inactivation of cyclin T1 from P-TEFb abolished the transcription of AIRE-responsive genes and led to lymphocytic infiltration of lacrimal and salivary glands in the CycT1 ؊/؊ mouse. Our findings reveal critical steps by which AIRE regulates the transcription of genes that control central tolerance in the thymus.

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Section: Discussionmentioning

confidence: 99%

AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells

Oven

Brdičková

Kohoutek

et al. 2007

Molecular and Cellular Biology

142

131

View full text Add to dashboard Cite

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“…Several XL sequences identified between HLA-DRA and HLA-DRB3 were found to be functionally important based on their ability to bind RFX and CIITA in vivo, and drive expression of a reporter gene. 60 Furthermore, Gomez et al (2005) 60 identified a structural interaction between an upstream XL-sequence and the HLA-DRA promoter using a chromatin-looping assay. Strikingly, it appears that certain XL sequences can contribute to a global increase in chromatin accessibility of the class II region and interact with proximal promoter regulatory sequences through DNA looping.…”

Section: Sxy-like Sequences and Mhc Class II Gene Regulationmentioning

confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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“…ChIP Assays-ChIP assays were performed as described previously in Beresford and co-workers (15,25). Cells were cross-linked with formaldehyde for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…These include the discovery of a potential locus control region located upstream of the MHC class II gene HLA-DRA (14). A recent search of the MHC-II locus identified additional X-Y box sequences that were not associated with functional MHC class II genes and were termed X-like (XL) boxes (15). The analysis of these sequences by chromatin immunoprecipitation (ChIP) indicated that some of them were functional as determined by their ability to bind RFX and CIITA, to drive the expression of a reporter gene, and to be associated with chromatin modifications that were similar to active MHC-II gene proximal promoter regions.…”

Section: The Human Major Histocompatibility Complex (Mhc)mentioning

confidence: 99%

The Human Major Histocompatibility Complex Class II HLA-DRB1 and HLA-DQA1 Genes Are Separated by a CTCF-binding Enhancer-blocking Element

Majumder¹,

Gómez²,

Boss

2006

Journal of Biological Chemistry

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The human major histocompatibility complex class II (MHC-II) region encodes a cluster of polymorphic heterodimeric glycoproteins HLA-DR, -DQ, and -DP that functions in antigen presentation. Separated by ϳ44 kb of DNA, the HLA-DRB1 and HLA-DQA1 encode MHC-II proteins that function in separate MHC-II heterodimers and are diametrically transcribed. A region of high acetylation located in the intergenic sequences between HLA-DRB1 and HLA-DQA1 was discovered and termed XL9. The peak of acetylation coincided with sequences that bound the insulator protein CCCTC-binding factor as determined by chromatin immunoprecipitations and in vitro DNA binding studies. XL9 was also found to be associated with the nuclear matrix. The activity of the XL9 region was examined and found to be a potent enhancer-blocking element. These results suggest that the XL9 region may have evolved to separate the transcriptional units of the HLA-DR and HLA-DQ genes.The human major histocompatibility complex (MHC) 3 encodes a dense cluster of genes that spans almost 4 megabases of human chromosome 6 (1). The MHC is divided into the following three regions: class I, II, and III. Many of the genes encoded in these subregions function in adaptive and innate immunity. The MHC-II locus consists of a group of 7-10 highly polymorphic genes that code for the ␣ and ␤ chains of the classical MHC-II heterodimeric molecules (reviewed in Ref. 2). In total, three MHC class II isotypes HLA-DR, HLA-DQ, and HLA-DP can be formed. MHC class II molecules function by presenting antigenic peptides to CD4ϩ T lymphocytes and are critical to the development of the T cell repertoire and the proliferation and differentiation of antigen-specific CD4 T cells during adaptive immune responses (3, 4). This process is aided by two MHC class II-associated molecules, HLA-DM and -DO, which are also ␣/␤ heterodimers with sequence and structural homology to MHC-II proteins (5, 6).MHC-II genes are regulated in a cell type-specific manner and are constitutively expressed in B lymphocytes, macrophages, dendritic cells, and thymic epithelia (reviewed in Refs. 2 and 7). However, in response to interferon-␥, most other cell types can be induced to express MHC class II genes. Regulation of MHC class II genes is coordinated by a group of conserved sequence elements termed the W/Z, X1, X2, and Y boxes, located at a promoter proximal region upstream of all MHC-II genes. The factors RFX, CREB, and NF-Y bind cooperatively to the X1-X2-Y box sequences, respectively, but are not sufficient for gene expression (8 -10). Expression requires the class II transactivator, CIITA, a non-DNA binding co-activator (11). CIITA mediates interactions between the DNA-bound X-Y box factors, chromatin remodeling machinery, additional co-activators, and various components of the general transcription machinery to allow for MHC class II transcription (2, 7).Despite the requirement of the W-X-Y box conserved sequences for MHC class II gene expression, a number of observations suggest that other regulatory components ...

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X Box-Like Sequences in the MHC Class II Region Maintain Regulatory Function

Cited by 46 publications

References 44 publications

AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells

AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

The Human Major Histocompatibility Complex Class II HLA-DRB1 and HLA-DQA1 Genes Are Separated by a CTCF-binding Enhancer-blocking Element

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