Abstract
Tandem repeats (TRs) are generated by DNA replication errors and retain a high level of instability, which in principle would make them unsuitable for integration into gene regulatory networks. However, the appearance of DNA sequence motifs recognized by transcription factors may turn TRs into functional cis-regulatory elements, thus favoring their stabilization in genomes. Here, we show that, in human cells, the transcriptional repressor ZEB1, which promotes the maintenance of mesenchymal features largely by suppressing epithelial genes and microRNAs, occupies TRs harboring dozens of copies of its DNA-binding motif within genomic loci relevant for maintenance of epithelial identity. The deletion of one such TR caused quasi-mesenchymal cancer cells to reacquire epithelial features, partially recapitulating the effects of ZEB1 gene deletion. These data demonstrate that the high density of identical motifs in TRs can make them suitable platforms for recruitment of transcriptional repressors, thus promoting their exaptation into pre-existing cis-regulatory networks. Tandem repeats, iterated and unstable sequences generated by DNA replication errors, can be integrated into ancient gene regulatory networks controlling mesenchymal identity and stabilized in the human genome.
| Original language | English |
|---|---|
| Pages (from-to) | 1150-1164.e14 |
| Journal | Cell |
| Volume | 173 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 17 2018 |
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Keywords
- epithelial-to-mesenchymal transition
- gene regulatory networks
- gene repression
- pancreatic cancer
- repetitive elements
- tandem repeats
- ZEB1
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Co-optation of Tandem DNA Repeats for the Maintenance of Mesenchymal Identity. / Balestrieri, Chiara; Alfarano, Gabriele; Milan, Marta; Tosi, Valentina; Prosperini, Elena; Nicoli, Paola; Palamidessi, Andrea; Scita, Giorgio; Diaferia, Giuseppe R.; Natoli, Gioacchino.
In: Cell, Vol. 173, No. 5, 17.05.2018, p. 1150-1164.e14.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Co-optation of Tandem DNA Repeats for the Maintenance of Mesenchymal Identity
AU - Balestrieri, Chiara
AU - Alfarano, Gabriele
AU - Milan, Marta
AU - Tosi, Valentina
AU - Prosperini, Elena
AU - Nicoli, Paola
AU - Palamidessi, Andrea
AU - Scita, Giorgio
AU - Diaferia, Giuseppe R.
AU - Natoli, Gioacchino
PY - 2018/5/17
Y1 - 2018/5/17
N2 - Tandem repeats (TRs) are generated by DNA replication errors and retain a high level of instability, which in principle would make them unsuitable for integration into gene regulatory networks. However, the appearance of DNA sequence motifs recognized by transcription factors may turn TRs into functional cis-regulatory elements, thus favoring their stabilization in genomes. Here, we show that, in human cells, the transcriptional repressor ZEB1, which promotes the maintenance of mesenchymal features largely by suppressing epithelial genes and microRNAs, occupies TRs harboring dozens of copies of its DNA-binding motif within genomic loci relevant for maintenance of epithelial identity. The deletion of one such TR caused quasi-mesenchymal cancer cells to reacquire epithelial features, partially recapitulating the effects of ZEB1 gene deletion. These data demonstrate that the high density of identical motifs in TRs can make them suitable platforms for recruitment of transcriptional repressors, thus promoting their exaptation into pre-existing cis-regulatory networks. Tandem repeats, iterated and unstable sequences generated by DNA replication errors, can be integrated into ancient gene regulatory networks controlling mesenchymal identity and stabilized in the human genome.
AB - Tandem repeats (TRs) are generated by DNA replication errors and retain a high level of instability, which in principle would make them unsuitable for integration into gene regulatory networks. However, the appearance of DNA sequence motifs recognized by transcription factors may turn TRs into functional cis-regulatory elements, thus favoring their stabilization in genomes. Here, we show that, in human cells, the transcriptional repressor ZEB1, which promotes the maintenance of mesenchymal features largely by suppressing epithelial genes and microRNAs, occupies TRs harboring dozens of copies of its DNA-binding motif within genomic loci relevant for maintenance of epithelial identity. The deletion of one such TR caused quasi-mesenchymal cancer cells to reacquire epithelial features, partially recapitulating the effects of ZEB1 gene deletion. These data demonstrate that the high density of identical motifs in TRs can make them suitable platforms for recruitment of transcriptional repressors, thus promoting their exaptation into pre-existing cis-regulatory networks. Tandem repeats, iterated and unstable sequences generated by DNA replication errors, can be integrated into ancient gene regulatory networks controlling mesenchymal identity and stabilized in the human genome.
KW - epithelial-to-mesenchymal transition
KW - gene regulatory networks
KW - gene repression
KW - pancreatic cancer
KW - repetitive elements
KW - tandem repeats
KW - ZEB1
UR - http://www.scopus.com/inward/record.url?scp=85046168551&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046168551&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2018.03.081
DO - 10.1016/j.cell.2018.03.081
M3 - Article
AN - SCOPUS:85046168551
VL - 173
SP - 1150-1164.e14
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -