Long Noncoding RNA HCP5, a Hybrid HLA Class I Endogenous Retroviral Gene: Structure, Expression, and Disease Associations

Abstract

The HCP5 RNA gene (NCBI ID: 10866) is located centromeric of the HLA-B gene and between the MICA and MICB genes within the major histocompatibility complex (MHC) class I region. It is a human species-specific gene that codes for a long noncoding RNA (lncRNA), composed mostly of an ancient ancestral endogenous antisense 3' long terminal repeat (LTR, and part of the internal pol antisense sequence of endogenous retrovirus (ERV) type 16 linked to a human leukocyte antigen (HLA) class I promoter and leader sequence at the 5'-end. Since its discovery in 1993, many disease association and gene expression studies have shown that HCP5 is a regulatory lncRNA involved in adaptive and innate immune responses and associated with the promotion of some autoimmune diseases and cancers. The gene sequence acts as a genomic anchor point for binding transcription factors, enhancers, and chromatin remodeling enzymes in the regulation of transcription and chromatin folding. The HCP5 antisense retroviral transcript also interacts with regulatory microRNA and immune and cellular checkpoints in cancers suggesting its potential as a drug target for novel antitumor therapeutics.

Keywords: HCP5; HLA; MHC; autoimmune diseases; cancer; competing endogenous RNA (ceRNA); human endogenous retrovirus (HERV); human immunodeficiency virus (HIV); human papillomavirus (HPV); lncRNA.

Figure 1

Location of the HCP5 gene (d) within the ERV16 element (c) and the human leukocyte antigen (HLA) class I region of the beta-block (b) on chromosome 6 at 6p21.33 (a). The HLA class I promoter region (the green rectangle labeled as Pr) for the 2630 bp HCP5 gene (d) initiates transcription of the 2547 bp lnc HCP5 RNA (e). The 91 bp intron in the HCP5 gene is represented by the thin grey line between the violet rectangular lines (d). The AluSp, THE1B, and LTR162B insertions within the 6173 bp ERV16 sequence [30] (c) are indicated by the labeled circle, triangle, and rectangles, respectively (see Table 1 for more details). The H3K27Ac binding (orange curve) and Dnase I hypersensitivity region (grey horizontal rectangle) associated with the HCP5 gene sequence (d) and sourced from the University of California, Santa Cruz (UCSC) genomic browser (Table S1) are shown on line (f).

Figure 2

DNA nucleotide alignment between the papillomavirus minor structural protein (PMSP) (AJ437509.2) and HCP5 RNA sequence (NR_040662.1).

Figure 3

HCP5 (a) and HLA-B (b) RNA sequences in 27 different normal tissues from 95 human individuals. NCBI BioProject PREJEB4337. RPKM (reads per kilobase of transcript per million mapped reads) on the y-axis is a normalized unit of transcript expression [60].

Figure 4

CTCF-binding sites proximal to and within the HCP5 gene. (A) ENCODE accession number (EH37E1260344) and statistical scores for presence of binding sites for CTCF, H3K4me3, and H3K27ac and DNaseI hypersensitivity clusters. (B) The ENCODE regulation tracking details from the UCSC genome browser (Table S1) show the CTCF locations (blue horizontal blocks on line 3) relative to (C) the HCP5 and HLA-X gene positions below the horizontal red line. In (B) the cREs with a high probability for binding H3K4me3 are the red blocks on line 1, and those with high probability for binding H3K27ac are the yellow blocks on line 2. (D) The location of the DNaseI hypersensitivity clusters and 161 transcription factor binding sites from ChIP-seq data analysis archived in ENCODE are shown below the HLA-X and HCP5 genes.

Figure 5

HCP5 functional relationships in PathwayNet (Table S1) [137].