Transcriptional control of the HERV-H LTR element of the GSDML gene in human tissues and cancer cells

Abstract

Long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) have been reported to serve as alternative promoters in functional genes. The GSDML (gasdermin-like protein) gene located on human chromosome 17q21 has been found to be an oncogenomic recombination hotspot. Here, we identified the LTR element of HERV-H with reverse orientation as an alternative promoter of the GSDML gene and analyzed its expression pattern in human tissues and cancer cells. A reporter gene assay of the promoter activity of the LTR on the GSDML gene in human cancer cell lines (HCT-116 and HeLa) and a kidney cell line (Cos7) of African green monkey indicated that the LTR promoter with reverse orientation had stronger promoter activity than forward one. The transcripts of this LTR-derived promoter were widely distributed in various human tissues and cancer cells, whereas the transcripts of the cellular promoter were found only in stomach tissues and some cancer cells (HCT116, MCF7, U937, C-33A, and PC3). These findings suggest that the LTR element on the GSDML gene was integrated into the hominoid lineage and acquired the role of transcriptional regulation of human tissues and cancer cells.

Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB)

“…GSDMB promoter directing expression in the gastric epithelium Sin et al (2006) indicated that GSDMB has two promoters, a cellular promoter and an LTRderived promoter and that these promoters are used selectively in normal gastric epithelium and gastric cancer cells, respectively. Although transcriptional activity of the LTR-derived promoter has been defined (Huh et al, 2008), that of cellular promoter has been elusive (Fig.…”

“…Analysis of GSDMB cellular promoter constructs in MKN74 cell line. (A) Schematic representation of the cellular and LTR-derived promoters responsible for GSDMB expression (Sin et al, 2006). Translation initiation site is indicated by ATG.…”

“…Although GSDMA and GSDMB belong to the same gene family and are located near to each other on 17q21, expression of GSDMA and GSDMB during cancer development and progression are non-overlapping and complementary. It was reported that there are two different promoters in the cis-regulatory elements of GSDMB, a cellular promoter and a long-terminal-repeat (LTR)-derived promoter (Sin et al, 2006;Huh et al, 2008). These two promoters share all GSDMB exons except for exon1a and exon1b, respectively, but they direct different expression patterns depending on the type of tissue or cancer.…”

“…These two promoters share all GSDMB exons except for exon1a and exon1b, respectively, but they direct different expression patterns depending on the type of tissue or cancer. According to reports, the LTR-derived promoter directs GSDMB expression in various types of cancer and normal tissues excluding stomach, and the cellular promoter directs expression solely in normal stomach tissues (Sin et al, 2006). Subsequent reports confirmed the finding on the activity of the LTR-derived promoter (Huh et al, 2008); however, the molecular mechanisms by which the cellular promoter regulates GSDMB expression in gastric epithelium have not yet been elucidated.…”

Human endogenous retrovirus K14C drove genomic diversification of the Y chromosome during primate evolution

“…Many reports demonstrate that HERV sequences regulate expression of functional genes near the site of integration. [12][13][14] An ancient member of HERV-K family entered the genome in the Old World monkey lineage but HERV-K recurrently amplified and expanded during primate evolution. 15 Some of HERV-K members are present only in chimpanzees and humans, indicating a relatively recent integration event within in the last five to eight million years.…”