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Mapping of FOXA1 Binding Reveals How it Differentially Regulates Gene Expression in Cancer

NEW YORK (GenomeWeb) – Mayo Clinic researchers have examined how the transcription factor FOXA1 creates cell-specific genomic signatures and differentially regulates gene expression in cancer.

Through chromatin immunoprecipitation and high-throughput sequencing, the Mayo team led by Zhaoyu Li mapped FOXA1 binding in four human cancer cell lines. While most of the genes targeted by FOXA1 binding were common across the four lines, most of the functional target genes were actually specific to each cancer cell type, as the team reported today in Science Advances.

Using gene-editing and other tools, the team further reported that cell-specific FOXA1 functions were due to unique FOXA1 binding as well as to genetic variations and epigenetic regulation.

Within the four cancer cell types the researchers mapped — the liver cancer cell line HepG2, the prostate cancer cell line LNCaP, and two breast cancer cell lines MCF7 and T47D — the researchers uncovered between 68,000 and 89,000 FOXA1 binding peaks. About half those peaks were unique to each cell line, but most of the FOXA1 target genes associated with those peaks were common across the four cancer cell lines.

Each FOXA1 target gene, Li and his colleagues further reported, was linked with multiple FOXA1 binding peaks. Still, they found that some peaks were unique to a single gene in one cell line, while sometimes multiple common peaks were associated with a single gene in more than one cell line, among other combinations. This, the researchers said, suggests that most cell-specific FOXA1 regulation is due to differential FOXA1 binding at the target gene's regulatory region.

By focusing on FOXA1 binding peaks linked with functional and direct FOXA1 target genes, Li and his colleagues also found that 14 percent to 22 percent of these FOXA1 binding peaks were unique to each cancer cell line, and that these functional target genes were regulated by both common and unique peaks.

This, the researchers said, suggests that the uniqueness of functional FOXA1 targeting in each cell line is determined by either those unique FOXA1 binding peaks or by common FOXA1 binding peaks that can turn FOXA1 target gene transcription off and on in a cell-specific manner.

Gene variants at FOXA1 binding sites also influence FOXA1 binding, the researchers reported. Through deep sequencing, they came up with some 4 million SNVs per cell line, about a quarter of which were common across the lines. But of these, nearly 2,500 SNVs could affect the FOXA1 binding element motif.

By overlapping those SNVs with the FOXA1 direct target gene data, the researchers found 256 functional FOXA1 target genes that could be affected by these variants. Most of these, they said, were unique to each cell line.

These FOXA1 target genes, the researchers further noted are enriched for functions in cell proliferation, growth, death, and survival.

Similarly, the researchers analyzed whether differences in epigenetic regulation could affect cell-specific FOXA1 targeting. Of eight histone markers, they found that five were enriched near FOXA1 binding sites, but only four exhibited cell-specific enrichment.

Overall, this indicated to Li and his colleagues that there is unique FOXA1 targeting in each cancer cell type and that the regulation of FOXA1 is determined by the binding of FOXA1, which is itself influenced by genetic variants at the cis-regulatory elements and by epigenetic regulation near FOXA1 binding sites.

Based on this, they proffered a "flower-blooming" hypothesis. "The 'blooming' (functioning) of a transcription factor in a cell-specific manner could be controlled by its unique binding, genetic variations, epigenetic regulation, and other factors, including co-regulators and chromatin remodeling," they wrote, noting that the process resembles that of flowers blooming.