Apolipoprotein(a) Gene Enhancer Resides within a LINE Element

Abstract

Apolipoprotein(a), (apo(a)), is the distinguishing protein portion of the lipoprotein(a) particle, elevated plasma levels of which are a major risk factor for cardiovascular disease. A search for enhancer elements that control the transcription of the apo(a) gene led to the identification of an upstream element that contains target binding sites for members of the Ets and Sp1 nuclear protein families. The enhancer element functions in either orientation to confer a greater than 10-fold increase in the activity of the apo(a) minimal promoter in cultured hepatocyte cells. Unexpectedly, the enhancer element is located within a LINE retrotransposon element, suggesting that LINE elements may function as mobile regulatory elements to control the expression of nearby genes.

Antisense Promoter of Human L1 Retrotransposon Drives Transcription of Adjacent Cellular Genes

“…Figure 8 shows multiple sequence alignment of the L1Hs ASP region from nt 394 to 607 derived from the genomic clones. The most critical region of 68 bp (from PstI-StuI site) required for the ASP activity determined here encompasses two previously known footprints, VI and VII, sequences of which contain binding sites for Sp1 (40) and SOX transcription factors (36). Four of the 12 genomic ASP constructs had substitution mutations in the footprint VI region (with the exception of construct 11A) and showed reduced promoter activity (constructs 17A, 27A, 15A, and 22A VOL.…”

“…The marginal location of a mutation in construct 11A apparently had no major impact on promoter activity. It should be noted, however, that the Pst-Nhe region contains several DNA footprints (40), which makes the precise assignment of transcription regulatory regions rather difficult. In addition, binding sites for SOX transcription factors involved in the sense L1Hs promoter activity (36) and a binding site of the Ets enhancer (40) have been previously determined.…”

“…It should be noted, however, that the Pst-Nhe region contains several DNA footprints (40), which makes the precise assignment of transcription regulatory regions rather difficult. In addition, binding sites for SOX transcription factors involved in the sense L1Hs promoter activity (36) and a binding site of the Ets enhancer (40) have been previously determined. Therefore, it is unclear which regions, besides nt 399 to 467, may be involved in the binding of transcription factors.…”

“…To define the L1Hs ASP more precisely, I took advantage of the previous promoter activity data for 12 randomly selected genomic L1Hs 5ЈUTRs (described above) and the DNase footprinting data of others (40). Figure 8 shows multiple sequence alignment of the L1Hs ASP region from nt 394 to 607 derived from the genomic clones.…”

“…Besides an internal promoter, the L1Hs 5ЈUTR contains an enhancer located around nt ϩ500. As revealed by deletion, mutation, and DNase footprinting analyses, its activation in-volves Ets and possibly other transcription factors, including Sp1 (40). In the human genome, the presence of about 4,000 full-length copies of the L1Hs containing enhancer elements in the 5ЈUTR suggests an exceptional power of these retrotransposons to regulate the expression of nearby genes.…”