Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach

Wong, Daniel; Humburg, Peter; Makino, Seiko; Lau, Evelyn; Naranbhai, Vivek; Fairfax, Benjamin P.; Chan, Kenneth; Plant, Katharine; Knight, Julian C.

doi:10.1186/preaccept-3072014071278914

Cited by 7 publications

(6 citation statements)

References 29 publications

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“…In addition, an eGWAS performed on blood from cohorts of healthy women and breast cancer survivors showed an association between ten HLA genes ( HLA-C , HLA-E , HLA-F , HLA-G , HLA-H , HLA-DPB1 , HLA-DQA1 , HLA-DQB1 , HLA-DRB3 , HLA-DRB4 ) and SNPs in 100 genes located on human chromosome 6 [ 37 ]. In particular, CIITA has been identified as a master trans -activator, with an essential role in initiating transcription of MHC class II genes in human stimulated B cells and monocytes [ 38 ]. However, our eGWAS did not generate any evidence of CIITA acting as a master regulator, despite the presence of one CIITA -related SNP on the array.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the genetic regulation of peripheral blood transcriptome in pigs through expression genome-wide association study and allele-specific expression analysis

et al. 2017

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BackgroundEfforts to improve sustainability in livestock production systems have focused on two objectives: investigating the genetic control of immune function as it pertains to robustness and disease resistance, and finding predictive markers for use in breeding programs. In this context, the peripheral blood transcriptome represents an important source of biological information about an individual’s health and immunological status, and has been proposed for use as an intermediate phenotype to measure immune capacity. The objective of this work was to study the genetic architecture of variation in gene expression in the blood of healthy young pigs using two approaches: an expression genome-wide association study (eGWAS) and allele-specific expression (ASE) analysis.ResultsThe blood transcriptomes of 60-day-old Large White pigs were analyzed by expression microarrays for eGWAS (242 animals) and by RNA-Seq for ASE analysis (38 animals). Using eGWAS, the expression levels of 1901 genes were found to be associated with expression quantitative trait loci (eQTLs). We recovered 2839 local and 1752 distant associations (Single Nucleotide Polymorphism or SNP located less or more than 1 Mb from expression probe, respectively). ASE analyses confirmed the extensive cis-regulation of gene transcription in blood, and revealed allelic imbalance in 2286 SNPs, which affected 763 genes. eQTLs and ASE-genes were widely distributed on all chromosomes. By analyzing mutually overlapping eGWAS results, we were able to describe putative regulatory networks, which were further refined using ASE data. At the functional level, genes with genetically controlled expression that were detected by eGWAS and/or ASE analyses were significantly enriched in biological processes related to RNA processing and immune function. Indeed, numerous distant and local regulatory relationships were detected within the major histocompatibility complex region on chromosome 7, revealing ASE for most class I and II genes.ConclusionsThis study represents, to the best of our knowledge, the first genome-wide map of the genetic control of gene expression in porcine peripheral blood. These results represent an interesting resource for the identification of genetic markers and blood biomarkers associated with variations in immunity traits in pigs, as well as any other complex traits for which blood is an appropriate surrogate tissue.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4354-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Deciphering the genetic regulation of peripheral blood transcriptome in pigs through expression genome-wide association study and allele-specific expression analysis

et al. 2017

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“…The high specificity of NLRC5 for a small number of phylogenetically related MHCI genes is strikingly similar to that of CIITA, for which ChIP-on-microarray experiments have revealed high selectivity for genes involved in MHCII-mediated antigen presentation [ 12 ]. Although recent ChIP-seq experiments have suggested that there are other CIITA-occupied sites in the genome [ 27 ], their functional relevance remains to be demonstrated. The extremely focused activity of NLRC5 and CIITA sets them apart from other transcription factors and transcriptional coactivators, which typically regulate hundreds or thousands of genes and exhibit much more diverse and pleiotropic functions; these two NLRs are instead specialized for the expression of only few phylogenetically and/or functionally related genes, representing a novel type of highly dedicated transcriptional regulator.…”

Section: Discussionmentioning

confidence: 99%

NLRC5 Exclusively Transactivates MHC Class I and Related Genes through a Distinctive SXY Module

et al. 2015

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MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) family member CIITA, which is recruited to SXY enhancers of MHCII promoters via a DNA-binding “enhanceosome” complex. NLRC5, another NLR protein, was recently found to control transcription of MHC class I (MHCI) genes. However, detailed understanding of NLRC5’s target gene specificity and mechanism of action remained lacking. We performed ChIP-sequencing experiments to gain comprehensive information on NLRC5-regulated genes. In addition to classical MHCI genes, we exclusively identified novel targets encoding non-classical MHCI molecules having important functions in immunity and tolerance. ChIP-sequencing performed with Rfx5−/− cells, which lack the pivotal enhanceosome factor RFX5, demonstrated its strict requirement for NLRC5 recruitment. Accordingly, Rfx5-knockout mice phenocopy Nlrc5 deficiency with respect to defective MHCI expression. Analysis of B cell lines lacking RFX5, RFXAP, or RFXANK further corroborated the importance of the enhanceosome for MHCI expression. Although recruited by common DNA-binding factors, CIITA and NLRC5 exhibit non-redundant functions, shown here using double-deficient Nlrc5−/−CIIta−/− mice. These paradoxical findings were resolved by using a “de novo” motif-discovery approach showing that the SXY consensus sequence occupied by NLRC5 in vivo diverges significantly from that occupied by CIITA. These sequence differences were sufficient to determine preferential occupation and transactivation by NLRC5 or CIITA, respectively, and the S box was found to be the essential feature conferring NLRC5 specificity. These results broaden our knowledge on the transcriptional activities of NLRC5 and CIITA, revealing their dependence on shared enhanceosome factors but their recruitment to distinct enhancer motifs in vivo. Furthermore, we demonstrated selectivity of NLRC5 for genes encoding MHCI or related proteins, rendering it an attractive target for therapeutic intervention. NLRC5 and CIITA thus emerge as paradigms for a novel class of transcriptional regulators dedicated for transactivating extremely few, phylogenetically related genes.

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“…By applying more stringent selection, 53 and 20 of the above loci could be found in three to four or all datasets, respectively. While this work was in progress, an independent CIITA ChIP-seq on human B cells was published ( 69 ). In that study, only the Diagenode antiserum was used and 843 CIITA loci were identified, which had significant overlap with the data presented herein.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide CIITA-binding profile identifies sequence preferences that dictate function versus recruitment

Scharer¹,

Choi²,

Barwick³

et al. 2015

Nucleic Acids Research

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The class II transactivator (CIITA) is essential for the expression of major histocompatibility complex class II (MHC-II) genes; however, the role of CIITA in gene regulation outside of MHC-II biology is not fully understood. To comprehensively map CIITA-bound loci, ChIP-seq was performed in the human B lymphoblastoma cell line Raji. CIITA bound 480 sites, and was significantly enriched at active promoters and enhancers. The complexity of CIITA transcriptional regulation of target genes was analyzed using a combination of CIITA-null cells, including a novel cell line created using CRISPR/Cas9 tools. MHC-II genes and a few novel genes were regulated by CIITA; however, most other genes demonstrated either diminished or no changes in the absence of CIITA. Nearly all CIITA-bound sites were within regions containing accessible chromatin, and CIITA's presence at these sites was associated with increased histone H3K27 acetylation, suggesting that CIITA's role at these non-regulated loci may be to poise the region for subsequent regulation. Computational genome-wide modeling of the CIITA bound XY box motifs provided constraints for sequences associated with CIITA-mediated gene regulation versus binding. These data therefore define the CIITA regulome in B cells and establish sequence specificities that predict activity for an essential regulator of the adaptive immune response.

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Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach

Cited by 7 publications

References 29 publications

Deciphering the genetic regulation of peripheral blood transcriptome in pigs through expression genome-wide association study and allele-specific expression analysis

Deciphering the genetic regulation of peripheral blood transcriptome in pigs through expression genome-wide association study and allele-specific expression analysis

NLRC5 Exclusively Transactivates MHC Class I and Related Genes through a Distinctive SXY Module

Genome-wide CIITA-binding profile identifies sequence preferences that dictate function versus recruitment

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