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.

Co-optation of Tandem DNA Repeats for the Maintenance of Mesenchymal Identity

Natoli, Gioacchino
2018

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.
ZEB1
epithelial-to-mesenchymal transition
gene regulatory networks
gene repression
pancreatic cancer
repetitive elements
tandem repeats
Adult
Animals
Base Sequence
Cell Line, Tumor
Chromatin Immunoprecipitation
Female
Gene Expression
Humans
Male
Mesenchymal Stem Cells
Mice
Mice, Nude
MicroRNAs
Middle Aged
Mouth Mucosa
Polymorphism, Single Nucleotide
Protein Binding
Tandem Repeat Sequences
Transcription Factors
Zinc Finger E-box-Binding Homeobox 1
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/59365
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