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

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Abstract

In vivo, a wild-type pattern of major histocompatibility complex (MHC) class II expression requires a locus control region (LCR). Whereas the role of promoter-proximal MHC class II regulatory sequences is well established, the function of the distal LCR remained obscure. We show here that this LCR is bound by the MHC class II-specific transactivators regulatory factor X (RFX) and class II transactivator (CIITA). Binding of these factors induces long-range histone acetylation, RNA polymerase II recruitment and the synthesis of extragenic transcripts within the LCR. The finding that RFX and CIITA regulate the function of the MHC class II LCR reveals an unexpected degree of complexity in the mechanisms controlling MHC class II gene expression.

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Acknowledgements

We thank A. Muhlethaler-Mottet for providing the pDRAprox plasmid; N. Hernandez and J. Svejstrup for providing antibodies; M. Zufferey and S. Landmann for help with cell culture and real-time PCR; and M. Strubin for valuable discussions. This work was supported by grants from the Swiss National Science Foundation and NovImmune SA.

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Competing interests

The authors declare no competing financial interests.

Correspondence to Walter Reith.

Supplementary information

  1. Supplementary Table 1 (PDF 51 kb)

  2. Supplementary Table 2 (PDF 47 kb)

  3. Supplementary Table 3 (PDF 39 kb)

  4. Supplementary Fig. 1 (PDF 536 kb)

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DOI

https://doi.org/10.1038/ni883

Further reading

Figure 1: Conserved regulatory elements situated upstream of mouse H2-Ea and human HLA-DRA.
Figure 2: The distal HLA-DRA Y'-S' module can function as a transcriptional enhancer.
Figure 3: The MHC class II transactivators RFX and CIITA occupy both the promoter proximal and distal enhancers of human HLA-DRA and murine H2-Ea.
Figure 4: Binding of RFX and CIITA induces a broad pattern of histone acetylation in the HLA-DRA upstream region.
Figure 5: RFX and CIITA recruit TFIID and TFIIB to the promoter, but not to the distal enhancer.
Figure 6: CIITA recruits Pol II to the HLA-DRA upstream region.
Figure 7: CIITA induces extragenic transcripts in the HLA-DRA upstream region.