HLA-G Expression in Human Mesenchymal Stem Cells (MSCs) Is Related to Unique Methylation Pattern in the Proximal Promoter as well as Gene Body DNA
Journal
International journal of molecular sciences
Journal Volume
21
Journal Issue
14
Date Issued
2020-07-18
Author(s)
Yen, B Linju
Hsu, Pei-Ju
Chen, Pei-Min
Wang, Li-Tzu
Jiang, Shih-Sheng
Liu, Ko-Jiunn
Sytwu, Huey-Kang
Abstract
Multipotent human mesenchymal stem cells (MSCs) harbor clinically relevant immunomodulation, and HLA-G, a non-classical MHC class I molecule with highly restricted tissue expression, is one important molecule involved in these processes. Understanding of the natural regulatory mechanisms involved in expression of this elusive molecule has been difficult, with near exclusive reliance on cancer cell lines. We therefore studied the transcriptional control of HLA-G in primary isolated human bone marrow- (BM), human embryonic stem cell-derived (hE-), as well as placenta-derived MSCs (P-MSCs), and found that all 3 types of MSCs express 3 of the 7 HLA-G isoforms at the gene level; however, fibroblasts did not express HLA-G. Protein validation using BM- and P-MSCs demonstrated expression of 2 isoforms including a larger HLA-G-like protein. Interferon-γ (IFN-γ) stimulation upregulated both gene and protein expression in MSCs but not the constitutively expressing JEG-3 cell line. Most interestingly in human MSCs and placental tissue, hypomethylation of CpG islands not only occurs on the HLA-G proximal promoter but also on the gene body as well, a pattern not seen in either of the 2 commonly used choriocarcinoma cell lines which may contribute to the unique HLA-G expression patterns and IFN-γ-responsiveness in MSCs. Our study implicates the importance of using normal cells and tissues for physiologic understanding of tissue-specific transcriptional regulation, and highlight the utility of human MSCs in unraveling the transcriptional regulation of HLA-G for better therapeutic application.
Subjects
DNA methylation; HLA-G; bone marrow (BM); embryonic stem cells (ESCs); gene body; human; interferon-γ (IFN-γ); mesenchymal stem cells (MSCs); placenta; promoter
SDGs
Other Subjects
HLA G antigen; messenger RNA; octamer transcription factor 4; small interfering RNA; transcription factor Sox2; trichostatin A; azacitidine; DNA; gamma interferon; HLA G antigen; isoprotein; Article; controlled study; cytotoxicity; DNA extraction; DNA methylation; embryonic stem cell; enzyme linked immunosorbent assay; epigenetics; fetus death; fibroblast; gene expression; gene silencing; genetic transfection; human; human cell; human tissue; immunomodulation; mesenchymal stem cell; phylogeny; placenta tissue; promoter region; protein expression; reverse transcription polymerase chain reaction; RNA extraction; RNA interference; tandem mass spectrometry; Western blotting; bone marrow cell; CpG island; cytology; demethylation; DNA methylation; drug effect; female; gene expression regulation; genetics; mesenchymal stem cell; metabolism; placenta; pregnancy; promoter region; tumor cell line; Azacitidine; Bone Marrow Cells; Cell Line, Tumor; CpG Islands; Demethylation; DNA; DNA Methylation; Embryonic Stem Cells; Female; Fibroblasts; Gene Expression Regulation; HLA-G Antigens; Humans; Interferon-gamma; Mesenchymal Stem Cells; Placenta; Pregnancy; Promoter Regions, Genetic; Protein Isoforms; Tandem Mass Spectrometry
Publisher
MDPI
Type
journal article