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PTGS2 ANTISENSE NFKB1 COMPLEX-MEDIATED EXPRESSION REGULATOR RNA, NONCODING; PACERR

PTGS2 ANTISENSE NFKB1 COMPLEX-MEDIATED EXPRESSION REGULATOR RNA, NONCODING; PACERR

Alternative titles; symbolsLONG NONCODING RNA PACERRlnRNA PACERRp50-ASSOCIATED COX2 EXTRAGENIC RNA; PACERPTGS2 ANTISENSE RNA 1; PTGS2AS1HGNC Approved Gene Symbol...

Alternative titles; symbols

  • LONG NONCODING RNA PACERR
  • lnRNA PACERR
  • p50-ASSOCIATED COX2 EXTRAGENIC RNA; PACER
  • PTGS2 ANTISENSE RNA 1; PTGS2AS1

HGNC Approved Gene Symbol: PACERR

Cytogenetic location: 1q31.1 Genomic coordinates (GRCh38): 1:186,680,653-186,681,445 (from NCBI)

▼ Description
Long noncoding RNAs (lncRNAs) contain more than 200 nucleotides and have no protein-coding potential. PACERR is a lncRNA that activates expression of the COX2 gene (PTGS2; 600262) (Krawcyzk and Emerson, 2014).

▼ Cloning and Expression
By chromatin immunoprecipitation experiments with primary human mammary epithelial cells, followed by quantitative RT-PCR and RACE, Krawcyzk and Emerson (2014) identified PACERR, which they called PACER, as an expressed antisense lncRNA originating from the upstream promoter region of the COX2 gene. They identified at least 4 PACER variants, the longest of which contains 765 bp. All 4 variants have a polyadenylation signal, and 3-prime RACE confirmed the presence of a poly(A) tail. Bioinformatic analysis provided no evidence that PACER encodes a functional protein. Biochemical fractionation of PACER-expressing human U987 macrophages showed that the majority of PACER transcripts localized to nucleus.

▼ Gene Function
Krawcyzk and Emerson (2014) found that expression of PACER and COX2 was reduced following small interfering RNA (siRNA)-mediated knockdown of CTCF (604167) in human mammary epithelial cells, suggesting that CTCF establishes an open chromatin domain to permit expression of the locus. Knockdown of PACER via siRNA decreased COX2 expression levels but did not alter CTCF binding at the COX2 promoter, indicating that PACER itself regulates COX2 mRNA expression. PACER knockdown significantly reduced histone H3 (see 602810) and H4 (see 602822) acetylation upstream of the COX2 gene. Binding of p300 (EP300; 602700) to the COX2 promoter was also significantly reduced by PACER knockdown, suggesting that promotion of histone acetylation by PACER is mediated by p300 recruitment. PACER knockdown also reduced RNA polymerase II (pol II; see 180660) complex association with the COX2 promoter. RNA immunoprecipitation revealed that PACER interacted directly with p50 (164011), the small subunit of NF-kappa-B, and PACER knockdown resulted in increased levels of bound p50 within the COX2 promoter. Krawcyzk and Emerson (2014) proposed that PACER regulates COX2 expression by restricting p50 binding at the COX2 promoter, thereby facilitating recruitment of p300, induction of histone acetylation, and assembly of pol II complexes to allow for transcriptional activation.

Using real-time PCR, Qian et al. (2016) demonstrated that PACER expression levels were elevated in human osteosarcoma tissues and cell lines relative to matched nontumor tissue and normal osteoblast cells, respectively. Bisulfite sequencing showed that CpG sites in the COX2 promoter were hypomethylated in osteosarcoma cells. PACER knockdown via short hairpin RNA resulted in reduced viability and invasive capability of 134B and MG63 human osteosarcoma cells. PACER knockdown also significantly downregulated COX2 expression. The effects of PACER knockdown on cell proliferation and viability were rescued by COX2 overexpression, suggesting that, in osteosarcoma, PACER function is mediated by COX2. Qian et al. (2016) proposed that PACER-driven COX2 activation may contribute to osteosarcoma cell proliferation and metastasis.

▼ Mapping
Gross (2017) mapped the PACERR gene to chromosome 1q31.1 based on an alignment of the PACERR sequence (GenBank NR_125801) with the genomic sequence (GRCh38).

Krawcyzk and Emerson (2014) determined that the PACERR gene is located in the upstream promoter region of the COX2 gene in the antisense orientation.

▼ Nomenclature
Krawcyzk and Emerson (2014) noted that the lncRNA PACERR should not be confused with the lncRNA COX2 (615492). The lncRNA COX2 is located downstream of the COX2 gene and has no functional relationship with COX2, whereas PACERR is located upstream of the COX2 gene and regulates COX2 expression.

Tags: 1q31.1