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

Krawczyk, Michał; Peyraud, Nicolas; Rybtsova, Natalia; Masternak, Krzysztof; Bücher, Philipp; Barras, Emmanuèle; Reith, Walter

doi:10.4049/jimmunol.173.10.6200

Cited by 61 publications

(77 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This could suggest that all MHC-II genes have an upstream element. Although our search did not identify other XL boxes in close (2-4 kb) proximity to the other MHC-II genes, a recent report (44) identified one upstream of the HLA-DRB1 gene that bound RFX and CIITA. This report did not pick up the any of the XL boxes that we found, pointing out the limitations associated with DNA search parameters.…”

Section: Figurementioning

confidence: 96%

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

Gómez

Majumder

Nagarajan

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

Sequences homologous to the canonical MHC class II (MHC-II) gene X box regulatory elements were identified within the HLA-DR subregion of the human MHC and termed X box-like (XL) sequences. Several XL box sequences were found to bind the MHC class II-specific transcription factors regulatory factor X and CIITA and were transcriptionally active. The histone code associated with the XL boxes and that of the HLA-DRA X box was determined. Using CIITA-positive and -negative B cell lines, CIITA-specific histone modifications were identified and found to be consistent among the active XL boxes. Although a remarkable similarity was observed for most modifications, differences in magnitude between the HLA-DRA promoter for modifications associated with the assembly of the general transcription factors, such as histone H3 lysine 9 acetylation and H3 lysine 4 trimethylation, distinguished the very active HLA-DRA promoter from the XL box regions. In response to IFN-γ, XL box-containing histones displayed increased acetylation, coincident with CIITA expression and that observed in B cells, suggesting that the end point mechanisms of chromatin remodeling for cell type-specific MHC-II expression were similar. Lastly, an interaction between one XL box and the HLA-DRA promoter was observed in a chromatin-looping assay. Therefore, these data provide evidence that certain XL box sequences contribute to a global increase in chromatin accessibility of the HLA-DR region in B lymphocytes and in response to IFN-γ and supports the involvement of these XL sequences in the regulation of MHC-II genes.

show abstract

Section: Figurementioning

confidence: 96%

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

Gómez

Majumder

Nagarajan

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…58 Several other distal SXY modules acting as transcriptional enhancers have been identified in the MHC class II region. 59 These distal SXY modules add another tier of complexity to class II gene regulation through long-distance control of expression. The notion that they have a tissue-specific role is intriguing and it will be of interest to analyze whether genetic variation in these distal elements can contribute to disease through cell-type-specific MHC class II expression defects.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…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 may exist (12,13). These include the discovery of a potential locus control region located upstream of the MHC class II gene HLA-DRA (14).…”

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

View full text Add to dashboard Cite

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 ...

show abstract

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

Cited by 61 publications

References 54 publications

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

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

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

Contact Info

Product

Resources

About