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Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach
BACKGROUND: The master transactivator CIITA is essential to the regulation of Major Histocompatibility Complex (MHC) class II genes and an effective immune response. CIITA is known to modulate a small number of non-MHC genes involved in antigen presentation such as CD74 and B2M but its broader genom...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243378/ https://www.ncbi.nlm.nih.gov/pubmed/25366989 http://dx.doi.org/10.1186/s13059-014-0494-z |
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author | Wong, Daniel Lee, Wanseon Humburg, Peter Makino, Seiko Lau, Evelyn Naranbhai, Vivek Fairfax, Benjamin P Chan, Kenneth Plant, Katharine Knight, Julian C |
author_facet | Wong, Daniel Lee, Wanseon Humburg, Peter Makino, Seiko Lau, Evelyn Naranbhai, Vivek Fairfax, Benjamin P Chan, Kenneth Plant, Katharine Knight, Julian C |
author_sort | Wong, Daniel |
collection | PubMed |
description | BACKGROUND: The master transactivator CIITA is essential to the regulation of Major Histocompatibility Complex (MHC) class II genes and an effective immune response. CIITA is known to modulate a small number of non-MHC genes involved in antigen presentation such as CD74 and B2M but its broader genome-wide function and relationship with underlying genetic diversity has not been resolved. RESULTS: We report the first genome-wide ChIP-seq map for CIITA and complement this by mapping inter-individual variation in CIITA expression as a quantitative trait. We analyse CIITA recruitment for pathophysiologically relevant primary human B cells and monocytes, resting and treated with interferon-gamma, in the context of the epigenomic regulatory landscape and DNA-binding proteins associated with the CIITA enhanceosome including RFX, CREB1/ATF1 and NFY. We confirm recruitment to proximal promoter sequences in MHC class II genes and more distally involving the canonical CIITA enhanceosome. Overall, we map 843 CIITA binding intervals involving 442 genes and find 95% of intervals are located outside the MHC and 60% not associated with RFX5 binding. Binding intervals are enriched for genes involved in immune function and infectious disease with novel loci including major histone gene clusters. We resolve differentially expressed genes associated in trans with a CIITA intronic sequence variant, integrate with CIITA recruitment and show how this is mediated by allele-specific recruitment of NF-kB. CONCLUSIONS: Our results indicate a broader role for CIITA beyond the MHC involving immune-related genes. We provide new insights into allele-specific regulation of CIITA informative for understanding gene function and disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-014-0494-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4243378 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42433782014-11-26 Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach Wong, Daniel Lee, Wanseon Humburg, Peter Makino, Seiko Lau, Evelyn Naranbhai, Vivek Fairfax, Benjamin P Chan, Kenneth Plant, Katharine Knight, Julian C Genome Biol Research BACKGROUND: The master transactivator CIITA is essential to the regulation of Major Histocompatibility Complex (MHC) class II genes and an effective immune response. CIITA is known to modulate a small number of non-MHC genes involved in antigen presentation such as CD74 and B2M but its broader genome-wide function and relationship with underlying genetic diversity has not been resolved. RESULTS: We report the first genome-wide ChIP-seq map for CIITA and complement this by mapping inter-individual variation in CIITA expression as a quantitative trait. We analyse CIITA recruitment for pathophysiologically relevant primary human B cells and monocytes, resting and treated with interferon-gamma, in the context of the epigenomic regulatory landscape and DNA-binding proteins associated with the CIITA enhanceosome including RFX, CREB1/ATF1 and NFY. We confirm recruitment to proximal promoter sequences in MHC class II genes and more distally involving the canonical CIITA enhanceosome. Overall, we map 843 CIITA binding intervals involving 442 genes and find 95% of intervals are located outside the MHC and 60% not associated with RFX5 binding. Binding intervals are enriched for genes involved in immune function and infectious disease with novel loci including major histone gene clusters. We resolve differentially expressed genes associated in trans with a CIITA intronic sequence variant, integrate with CIITA recruitment and show how this is mediated by allele-specific recruitment of NF-kB. CONCLUSIONS: Our results indicate a broader role for CIITA beyond the MHC involving immune-related genes. We provide new insights into allele-specific regulation of CIITA informative for understanding gene function and disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-014-0494-z) contains supplementary material, which is available to authorized users. BioMed Central 2014-10-31 2014 /pmc/articles/PMC4243378/ /pubmed/25366989 http://dx.doi.org/10.1186/s13059-014-0494-z Text en © Wong et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Wong, Daniel Lee, Wanseon Humburg, Peter Makino, Seiko Lau, Evelyn Naranbhai, Vivek Fairfax, Benjamin P Chan, Kenneth Plant, Katharine Knight, Julian C Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach |
title | Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach |
title_full | Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach |
title_fullStr | Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach |
title_full_unstemmed | Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach |
title_short | Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach |
title_sort | genomic mapping of the mhc transactivator ciita using an integrated chip-seq and genetical genomics approach |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243378/ https://www.ncbi.nlm.nih.gov/pubmed/25366989 http://dx.doi.org/10.1186/s13059-014-0494-z |
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