Abstract
ChIP-seq has been commonly applied to identify genomic occupation of transcription factors (TFs) in a context-specific manner. It is generally assumed that a TF should have similar binding patterns in cells from the same or closely related tissues. Surprisingly, this assumption has not been carefully examined. To this end, we systematically compared the genomic binding of the cell cycle regulator FOXM1 in eight cell lines from seven different human tissues at binding signal, peaks and target genes levels. We found that FOXM1 binding in ER-positive breast cancer cell line MCF-7 are distinct comparing to those in not only other non-breast cell lines, but also MDA-MB-231, ER-negative breast cancer cell line. However, binding sites in MDA-MB-231 and non-breast cell lines were highly consistent. The recruitment of estrogen receptor alpha (ERα) caused the unique FOXM1 binding patterns in MCF-7. Moreover, the activity of FOXM1 in MCF-7 reflects the regulatory functions of ERα, while in MDA-MB-231 and non-breast cell lines, FOXM1 activities regulate cell proliferation. Our results suggest that tissue similarity, in some specific contexts, does not hold precedence over TF-cofactors interactions in determining transcriptional states and that the genomic binding of a TF can be dramatically affected by a particular co-factor under certain conditions.
Highlights
Transcription factors (TFs) are crucial proteins that mediate gene transcriptional regulation by binding to specific DNA sequences in all living organisms
We find that the inferred regulatory activity of FOXM1 is predictive of the survival of patients, and more interestingly, scores inferred based on FOXM1 targets from different cell lines provide complementary clinically related information -MCF-7 specific FOXM1 targets inform estrogen receptor (ER) activity while targets in other cell lines inform the proliferative ability of tumor cells
Comparative analyses at the signal, peak, and gene target levels consistently support that MCF-7 ChIP-seq experiments are highly similar to each other but exhibit little resemblance to MDA-MB-231, which is more similar to non-breast cell lines
Summary
Transcription factors (TFs) are crucial proteins that mediate gene transcriptional regulation by binding to specific DNA sequences in all living organisms. Chromatin immunoprecipitation followed by microarray hybridization (ChIP-chip) [2] or highthroughput DNA sequencing (ChIP-seq) [3] have become the most widely used methods to detect binding events of individual TFs across the entire genome [1, 4,5,6] These methods identify direct and indirect (through interacting with co-factors) binding sites of DNA-associated proteins of interest [4, 7, 8]. Borneman et al compared the pseudohyphal regulators STE12 and TEC1 binding sites in three yeast species, S. cerevisiae, S. mikatae, and S. bayanus under pseudohyphal conditions and reached a similar conclusion [11] Other than these comparative studies by experiments, computational studies based on systematic motif analysis indicated high www.impactjournals.com/oncotarget turnover rate of TF binding motifs in different organisms [12, 14]. Motif analyses indicate that the binding motifs associated with a TF is generally conserved across species, presumably due to the selective pressure imposed on its DNA binding domain [7]
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