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Cancer cell line specific co-factors modulate the FOXM1 cistrome
Yue Wang1,2, Matthew H Ung2, Tian Xia1
1School of Electronic Information and Communications, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
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.
Insights
Transcription factor (TF) binding patterns can differ significantly between cell types, even within the same tissue. Co-factor interactions, like estrogen receptor alpha (ERα), play a crucial role in determining TF binding and function.
Area of Science:
- Molecular Biology
- Genomics
- Cancer Research
Background:
- Chromatin immunoprecipitation sequencing (ChIP-seq) is widely used to map transcription factor (TF) binding sites.
- It is generally assumed that TFs exhibit similar binding patterns across related tissues, an assumption rarely tested.
- The cell cycle regulator FOXM1 is crucial in various cancers.
Purpose of the Study:
- To systematically compare the genomic binding patterns of FOXM1 across diverse human cell lines and tissues.
- To investigate the influence of co-factors, specifically estrogen receptor alpha (ERα), on FOXM1 binding.
- To understand how FOXM1 activity and function vary depending on cellular context.
Main Methods:
- Systematic comparison of FOXM1 ChIP-seq data across eight cell lines from seven human tissues.
- Analysis of binding signal, peak distribution, and target gene occupancy.
- Correlation of FOXM1 binding patterns with the presence and activity of ERα.
Main Results:
- FOXM1 binding patterns in the ER-positive MCF-7 breast cancer cell line were distinct from other cell lines, including the ER-negative MDA-MB-231.
- FOXM1 binding in MDA-MB-231 and non-breast cell lines showed high consistency.
- Estrogen receptor alpha (ERα) recruitment was identified as the cause for unique FOXM1 binding in MCF-7 cells.
- FOXM1 activity in MCF-7 reflected ERα regulatory functions, while in other cell lines, it regulated cell proliferation.
Conclusions:
- Tissue similarity is not always the primary determinant of TF binding patterns; TF-cofactor interactions can be more influential.
- Specific co-factors, such as ERα, can dramatically alter a TF's genomic binding and functional output.
- Understanding context-specific TF binding is critical for deciphering transcriptional regulation in different cell types and diseases.
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