Members of the SRY family regulate the human LINE retrotransposons

Abstract

LINEs are endogenous mobile genetic elements which have dispersed and accumulated in the genomes of most higher eukaryotes via germline transposition, with up to 100 000 copies for the human LINE-1 (L1H) sequences. Although severely repressed in most normal tissues, L1H is still functional, with evidence for both germline and somatic-essentially in tumors-transpositions. Yet, no transcription factor that could regulate their transcription and be responsible for their transposition has hitherto been described. Here we show that factors belonging to the family of the testis-determining factor gene SRY (the SOX family) can modulate L1H promoter activity over a 10-fold range in a transient transfection assay using a luciferase reporter gene. These effects depend on two functional SRY binding sites which can be identified within the L1H promoter via mobility shift assays. Induction of endogenous L1Hs upon ectopic expression of the SOX11 transcription factor is further demonstrated, thus strengthening the physiological relevance of these new-and highly dispersed-target sites for the otherwise unclassical transcription factors of the SRY family.

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

“…Con, consensus sequence. DNase footprints, marked above the sequences by brackets and roman numerals I to VII, and binding sites for SOX and Ets associated with these footprints are from data of others (36,40). 5Ј-terminal nucleotides of different cDNAs are mapped to the sequence positions by arrows.…”

“…Here, another aspect of interest is a compact and overlapping location of transcription factor binding sites in the 5ЈUTR. It has been determined that the 5ЈUTR from nt 400 to 600 contains two binding sites for SOX factors involved in the L1Hs sense transcription (36) and an enhancer element, containing binding sites for Ets and Sp1 factors, capable of functioning in either orientation (40). For antisense transcription, binding sites located in this region, determined from deletion and mutation analysis, can be found for transcription factor Sp1 (Fig.…”

“…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.…”

“…Therefore, additional factors may be involved in the regulation of cell type specificity. Several such factors belonging to the testis-determining factor SRY or SOX family have also been shown to modulate L1Hs promoter activity in a transfection assay (36). Two binding sites for the SOX family members were located between nt ϩ472 to ϩ477 and ϩ572 to ϩ577.…”

Involvement of retrotransposon L1 in stemness and cellular plasticity

“…A role for L1 in cancer is further supported by the observation that the L1 promoter is hypomethylated in many carcinomas (Tsutsumi, 2000). Expression of LINE retrotransposons correlates with that of sex determining region Y (SRY) family factors, and it has been demonstrated that SRY-box (SOX) factors regulate the L1 transposable elements (Tchenio, 2000). Here we have demonstrated that L1 ORF2p gene expression is correlated with expression of the SOX2 transcription factor, which is involved in maintaining the stemness phenotype (Leis, 2012).…”