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. 2007 Nov 20;104(47):18613-8.
doi: 10.1073/pnas.0703637104. Epub 2007 Nov 14.

Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53

Ting Wang  1 , Jue Zeng, Craig B Lowe, Robert G Sellers, Sofie R Salama, Min Yang, Shawn M Burgess, Rainer K Brachmann, David Haussler
Affiliations

Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53

Ting Wang et al. Proc Natl Acad Sci U S A. .

Abstract

The evolutionary forces that establish and hone target gene networks of transcription factors are largely unknown. Transposition of retroelements may play a role, but its global importance, beyond a few well described examples for isolated genes, is not clear. We report that LTR class I endogenous retrovirus (ERV) retroelements impact considerably the transcriptional network of human tumor suppressor protein p53. A total of 1,509 of approximately 319,000 human ERV LTR regions have a near-perfect p53 DNA binding site. The LTR10 and MER61 families are particularly enriched for copies with a p53 site. These ERV families are primate-specific and transposed actively near the time when the New World and Old World monkey lineages split. Other mammalian species lack these p53 response elements. Analysis of published genomewide ChIP data for p53 indicates that more than one-third of identified p53 binding sites are accounted for by ERV copies with a p53 site. ChIP and expression studies for individual genes indicate that human ERV p53 sites are likely part of the p53 transcriptional program and direct regulation of p53 target genes. These results demonstrate how retroelements can significantly shape the regulatory network of a transcription factor in a species-specific manner.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Experimental validation of selected candidates. (A) ChIP of p53 with semiquantitative PCR for four LTR elements near genes, after treatment with 5-FU (375 μM for 6 h). (B) Reverse transcriptase quantitative real-time PCR for four genes close to the four LTR elements of A and TP53AP1, after treatment with 5-FU (375 μM for 24 h), doxorubicin (0.6 μg/ml for 24 h), or UV irradiation (60 J/m2). (C) p53 reporter gene assays for five firefly luciferase constructs driven by selected LTR fragments, using the same treatments as in B. Error bars in B and C represent 95% confidence interval (≈2 SDs). Relative expression levels were scaled relative to the mean of p53 (−/−) with no treatment (designated as 1). p21 served as a positive control.
Fig. 2.
Fig. 2.
Estimated age of p53 site-containing ERV families. Insertion time of individual families of ERV LTRs is estimated by three methods. (A) Age of each LTR family, estimated by examining the presence of sequences in different species. 0 indicates no homologous hit, and 1 indicates that there are homologous hits. (B) Ages of near-complete ERVs, estimated by comparing their 5′ and 3′ LTR sequence divergence. Upper and lower bound were calculated by using a mutation rate of 2.3 × 10−9 and 5 × 10−9 substitutions per site per year, respectively. (C) Substitution rate, calculated by comparing individual fragments to the consensus by using the Jukes–Cantor formula (26). Fragments were grouped based on the presence of a p53 site and if they are solo LTRs, then the average and SD were calculated for each group. Branch length is taken from that of ref. .
Fig. 3.
Fig. 3.
Evolutionary pattern of LTR10B1 genomic copies. Genomic copies of LTR10B1 are aligned to the consensus sequence. (A) Multiple sequence alignments, clustered based on existence of a p53 site and the percentage identity to the consensus. The blue line in the middle is the consensus sequence, and the red stretch indicates the position of the reconstructed p53 site. Every copy above the blue line contains a predicted p53 site. Sequences that are placed closer to the consensus have higher sequence similarity. The nucleotides are color-coded. A, green; C, yellow; G, red; T, blue. The image was created with Jalview (20). (B) Frequency of coverage of the consensus sequence by the genomic copies. (C) Average percentage identity of each base in the consensus sequence that is aligned to multiple genomic copies.
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