Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

Abstract

Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of self-tolerance. 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 haplotype-specific 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.

Figure 1. Genes and genetic diversity in the MHC class II region

The classical MHC class I, class III and class II regions are shown at chromosome 6p21 together with a higher resolution plot showing the location of genes within the MHC class II region chr6:32,250,000-33,300,000 (hg18 build 36). Structural genomic variation from the Database of Genomic Variants are shown (copy number variants in orange, insertions/deletions dark green) together with location of microsatellites and sequence level variation in terms of single nucleotide polymorphisms and small insertions and deletions (indels) (dbSNP build 129). Images adapted from UCSC Genome Browser.

Figure 2. Regulation of MHC class II transcription

Schematic representation of transcriptional regulation for an MHC class II gene. The MHC class II enhanceosome is shown resulting from recruitment of different binding factors including RFX, CREB and NF-Y to the S, X, X2 and Y box sequences located in the proximal promoter region. This recruits the master regulator CIITA which directs transcription.

Figure 3. Major human HLA-DR haplogroups

Five haplogroups are shown denoted DR1, DR8, DR51, DR52 and DR53. These differ by the presence of an additional functional DRB gene (DRB3, DRB4 or DRB5) (shown in black) and a varying number of DRB pseudogenes (DRB2, DRB6, DRB7, DRB8 or DRB9) (shown in grey). The DRB1 allelic lineages can be resolved to five families which relate to the five main haplogroups: HLA-DRB1*01 and *10 (DR1), *08 (DR8), *15 and *16 (DR51), *03, *11, *13 and *14 (DR52), and *4, *7 and *9 (DR53). Gene transcript structure derived from Ensembl but note figure schematic rather than drawn to scale with respect to location.

Figure 4. Sequence conservation and regulatory elements in proximal promoter region of HLA-DRB1

(A) Evidence of haplotype specific sequence variation involving regulatory sequences in HLA-DRB1 involving both X and Y boxes. DR4, DR7 and DR9 (the DR53 haplogroup) contain the highest variability. Such variants may explain the observed allele specific differential expression at this locus. (B) Dendrogram showing the relationship between the regulatory regions obtained from a pairwise similarity score. In general, regulatory sequence clusters correspond to the different ancestral haplotype groups. The proximal promoter sequence of the DR8 haplotype shows high degrees of similarity to that of the DR52 haplotype. Another cluster of homologous sequences consists of DR4, DR7 and DR9 (the DR53 haplogroup) and seems to have evolved independently.

Figure 5. A conserved VDRE confers responsiveness to vitamin D to HLA-DRB1

Schematic illustrating the role of a proximal VDRE at the HLA-DRB1 gene which confers vitamin D responsiveness through binding of VDR/RXR.