Chromatin remodeling and extragenic transcription at the MHC class II locus control region

Masternak, Krzysztof; Peyraud, Nicolas; Krawczyk, Michał; Barras, Emmanuèle; Reith, Walter

doi:10.1038/ni883

Cited by 146 publications

(159 citation statements)

References 44 publications

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“…Importantly, this activity was CIITA dependent because there was no activity over the background in RJ2.2.5 cells, which lack CIITA. The finding that XL-4 could direct the expression of a reporter gene was similar to that observed previously (14). Therefore, these results suggest that RFX-and CIITA-binding XL boxes could play a role in the regulation of genes in their natural context.…”

Section: Rfx and Ciita-binding XL Boxes Can Drive The Expression Of Asupporting

confidence: 88%

“…Further analyses showed that some of the XL boxes (XL-7 and XL-8) were positioned upstream of ancient duplications bearing homology to the first exon of the HLA-DRB gene (29) and extending several kilobases downstream of exon 1. XL-4, located 2.3 kb upstream of the HLA-DRA gene, was identified previously as a X-Y box region and a potential locus control element (14). Whereas XL-1, -2, and -3 were located further upstream of the HLA-DRA gene, they and XL-5 and -6 were not associated with an identifiable gene fragment.…”

Section: Within the Human Mhcmentioning

confidence: 88%

“…This observation is consistent with the finding that RFX also binds to XL-4. Indeed, as mentioned above, XL-4, which lies 2.3 kb upstream of the HLA-DRA X box, was previously found to bind RFX and CIITA (14). For comparison, a similar ChIP analysis was performed for the HLA-DRA and HLA-DRB1 gene promoter proximal X box regions (termed DRA-X and DRB1-X, respectively), which were shown previously to bind these factors in vivo (11,13).…”

Section: Rfx and Ciita Occupy Some But Not All XL Boxesmentioning

confidence: 88%

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

Gómez

Majumder

Nagarajan

et al. 2005

The Journal of Immunology

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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.

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Section: Rfx and Ciita-binding XL Boxes Can Drive The Expression Of Asupporting

confidence: 88%

Section: Within the Human Mhcmentioning

confidence: 88%

Section: Rfx and Ciita Occupy Some But Not All XL Boxesmentioning

confidence: 88%

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

Gómez

Majumder

Nagarajan

et al. 2005

The Journal of Immunology

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“…54 A similar SXY motif was found B2.3-kb upstream of the orthologous human HLA-DRA gene 57 and shown to bind RFX and CIITA leading to induction of long-range histone acetylation, recruitment of RNA polymerase II and production of low levels of intergenic transcripts. 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.…”

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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“…For real-time quantitative PCR, 2 μl of the reverse transcription mix was combined with primers for HLA-DRA (Masternak et al, 2003) or beta-actin, and Reaction Mix (QuantiTect SYBR Green PCR kit; Qiagen Inc.). The reactions were carried out in an Opticon 2 real-time thermal cycler (MJ Research Inc., Reno, NV, USA).…”

Section: Quantitative Real-time Reverse Transcriptase Pcrmentioning

confidence: 99%

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

Al-Kandari

Jambunathan

Navalgund

et al. 2007

Molecular Immunology

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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.

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Chromatin remodeling and extragenic transcription at the MHC class II locus control region

Cited by 146 publications

References 44 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

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

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