Transcriptional and Posttranscriptional Regulations of theHLA-GGene

Abstract

HLA-G has a relevant role in immune response regulation. The overall structure of the HLA-G coding region has been maintained during the evolution process, in which most of its variable sites are synonymous mutations or coincide with introns, preserving major functional HLA-G properties. The HLA-G promoter region is different from the classical class I promoters, mainly because (i) it lacks regulatory responsive elements for IFN-γ and NF-κB, (ii) the proximal promoter region (within 200 bases from the first translated ATG) does not mediate transactivation by the principal HLA class I transactivation mechanisms, and (iii) the presence of identified alternative regulatory elements (heat shock, progesterone and hypoxia-responsive elements) and unidentified responsive elements for IL-10, glucocorticoids, and other transcription factors is evident. At least three variable sites in the 3′ untranslated region have been studied that may influence HLA-G expression by modifying mRNA stability or microRNA binding sites, including the 14-base pair insertion/deletion, +3142C/G and +3187A/G polymorphisms. Other polymorphic sites have been described, but there are no functional studies on them. The HLA-G coding region polymorphisms might influence isoform production and at least two null alleles with premature stop codons have been described. We reviewed the structure of the HLA-G promoter region and its implication in transcriptional gene control, the structure of the HLA-G 3′UTR and the major actors of the posttranscriptional gene control, and, finally, the presence of regulatory elements in the coding region.

Human Leukocyte Antigen-G Inhibits the Anti-Tumor Effect of Natural Killer Cells via Immunoglobulin-Like Transcript 2 in Gastric Cancer

“…We found that HLA-G was lower in all cell lines, which was consistent with previous studies [40]. Previous researches have demonstrated that HLA-G expression in ovarian cancer and melanoma decreased or even completely disappeared after long-term culture of fresh HLA-G positive tumor cells in vitro [57-60], suggesting that the expression of HLA-G in tumor cells is regulated by the tumor microenvironment [61]. In addition, by using flow cytometry, we found that tumor-infiltrating NK cells were mainly expressed in ILT2.…”

Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

“…Both modules are divergent in HLA-G, rendering the HLA-G 5′URR unique among HLA genes. 29,39 The known regulatory elements of HLA-G present distinctive structural characteristics and extend up to~1500-bp upstream of the first translated codon, instead of only 500 bp in other class I genes. These unusual features may be responsible for the non-classical transcriptional regulation of HLA-G and its restricted expression in specific tissues such as the trophoblast or thymic epithelial cells in nonpathological conditions.…”

“…The LCR region is critical for the HLA-G expression regarding when and where it should be expressed. 29 The extent of the region explored in previous and present sequencing surveys is represented by a gray bar for each study. (b) Nucleotide sequence variations identified in the previous and present sequencing surveys.…”

“…28 Finally, Costa et al 19 found a significant association between HLA-G 5′URR haplotypes (including notably the putatively functional − 1140 A4T SNV (rs115371574)) and implantation outcome in couples undergoing assisted reproduction treatment. Considering the unique features of the HLA-G 5′URR among HLA class I genes, 29 and the fact that nucleotide changes in the cis-acting regulatory elements of this region may determine its differential responsiveness to transcriptional factors, 30,31 further genetic investigations are needed to clarify the role of HLA-G 5′URR polymorphisms in the spatio-temporal expression profile of HLA-G.…”

HNRNPR Regulates the Expression of Classical and Nonclassical MHC Class I Proteins

“…The transcription processes regulating MHC gene expression were broadly investigated (8), and a few posttranscription regulators were discovered as well (9,10). However, whether RNAbinding proteins (RBPs) control the expression of classical and nonclassical MHC class I proteins is largely unexplored.…”