HLA-G unique promoter region: functional implications

Abstract

In contrast to the highly polymorphic HLA class Ia genes that exhibit a broad somatic tissue distribution, the restricted constitutive expression of HLA-G to trophoblast and a subset of thymic epithelial cells suggests tight transcriptional control of this MHC class Ib gene. Transactivation of MHC class I genes is mediated by three major regulatory modules present in their promoter region namely enhancer A, ISRE, and SXY. The 220-bp promoter sequence of HLA-G comprises modified enhancer A and SXY modules and lacks the ISRE which renders this gene unresponsive to NK-kappaB, IRF1, and class II transactivator DNA-binding factors. A number of other HLA-G upstream regulatory elements have recently been described. Using different transgenic HLA-G mouse models under the control of the HLA-G promoter, several groups have shown by in situ hybridization and/or qualitative or quantitative RT-PCR that constitutive HLA-G transcriptional expression in placental tissue decreased with gestational time. This suggests that once the placenta is fully formed, the functions of HLA-G might not be so crucial.

RREB-1 Is a Transcriptional Repressor of HLA-G

“…HLA-G gene promoter structure and mRNA have been previously published (21)(22)(23) and are reported in the NCBI database. HLA-G gene consists of exon 1 (5Ј-ATG) encoding the signal peptide, exons 2, 3, and 4 encoding ␣1, ␣2, and ␣3 extracellular domains, respectively and exon 5 encoding transmembrane domain and a very short cytoplasmic tail together with exon 6.…”

“…HLA-G gene transcriptional machinery has been poorly described even if some of the mechanisms that govern HLA-G transcriptional activity have been identified (23 3 has been found located Ϫ1.2 kb from the ATG translation start site (20,(32)(33)(34) (named "distal promoter" region). A few HLA-G promoter binding factors and their target sites have been characterized such as CREB1 (28), IFN regulatory factor 1 (35), heat shock transcription factor 1 (36), or progesterone receptor (37).…”

Cutting Edge: Monarch-1: A Pyrin/Nucleotide-Binding Domain/Leucine-Rich Repeat Protein That Controls Classical and Nonclassical MHC Class I Genes

“…A series of conserved upstream DNA sequences in the classical MHC-I promoter include the AP-1 site (20), the NF-B site, the IFN regulatory factor (IRF) binding site, and the S-X-Y module shared with MHC-II promoters (15). In contrast, nonclassical MHC gene upstream elements exhibit nucleotide sequence variations, mutations, and deletions in these regions (21). It will be of significant interest to identify the Monarch-1 responsive regulatory DNA.…”

Modulation of HLA-G Expression in Human Neural Cells after Neurotropic Viral Infections

“…HLA-G induces tolerance-mediating dendritic cells by disrupting the major histocompatibility complex class II presentation pathway (61). Expression of the gene encoding HLA-G is regulated in a complex manner (8,44,46,66) by several cytokines, including beta interferon (IFN-␤) and IFN-␥ (11,31,32,34,36,42,60,70,74). The expression of this gene is also modulated by glucocorticosteroid treatment (43) and stress (24).…”