Research ArticleGENETICS

FOXA1 defines cancer cell specificity

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Science Advances  18 Mar 2016:
Vol. 2, no. 3, e1501473
DOI: 10.1126/sciadv.1501473
  • Fig. 1 Cell-specific FOXA1 targeting in human cancers.

    (A) Heatmap analysis of FOXA1 binding in human cancer cells. (B) FOXA1-associated genes from ChIP-Seq data are mostly common to human cancer cells. (C) Functional and direct FOXA1 target genes are mostly unique to each cancer cell line. (D and E) FOXA1 binding is disrupted (D) and expression of FOXA1 target genes is reversed (E) by CRISPR-mediated genome editing at selected FOXA1 binding sites. P < 0.05 for all assays between the control group and the CRISPR group. Data are means ± SEM.

  • Fig. 2 Unique FOXA1 targeting mediated by genetic variants.

    (A) Comparison of SNVs from the four cancer cell lines (HepG2, LNCaP, MCF7, and T47D) with SNP138. (B) SNV-introduced gain and loss of FOXA1 binding peaks. (C) Functional FOXA1 target genes associated with SNV-introduced gain and loss of FOXA1 binding sites. (D) Frequency of SNVs in the FOXA1 binding motifs for SNV-led motif loss or gain from (C) in all of the four cancer cell lines. (E) Example of SNV-introduced gain of FOXA1 binding sites targeting CEACAM5 in MCF7 cells.

  • Fig. 3 Correlations of histone modification with functional FOXA1 targeting.

    (A and B) Cell-specific enrichment of H3K27ac near functional (A) and cell-specific (B) FOXA1 binding peaks. (C) Example of H3K27ac enrichment near FOXA1 binding sites targeting XAF1 in HepG2 cells.

  • Fig. 4 Flower-blooming hypothesis for cell-specific transcriptional regulation.

    Cell-specific functioning of a transcription factor (TF) could be determined by unique binding of TF, genetic variants at TF binding sites, potential epigenomic regulation near TF binding sites, and/or other factors. TF regulation from highly common TF binding across cell types to cell-specific functional TF binding resembles the flower-blooming process. Triangle peaks represent TF binding.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/2/3/e1501473/DC1

    Materials and Methods

    Fig. S1. Cell-specific FOXA1 binding and targeting.

    Fig. S2. Five types of FOXA1 targeting in the four human cancer cell lines.

    Fig. S3. SNV-led gain or loss of FOXA1 binding and targeting.

    Fig. S4. Histone modification in cell-specific FOXA1 regulation.

    Table S1. Pathway analysis of functional FOXA1 target genes in human cancer cells by Ingenuity.

    Table S2. Genomic annotation of FOXA1 binding peaks in human cancer cells.

    Table S3. Whole genome sequencing data for human cancer cells.

    Table S4. Validation of SNV-introduced gain and loss of FOXA1 binding in human cancer cells.

    References (3238)

  • Supplementary Materials

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Cell-specific FOXA1 binding and targeting.
    • Fig. S2. Five types of FOXA1 targeting in the four human cancer cell lines.
    • Fig. S3. SNV-led gain or loss of FOXA1 binding and targeting.
    • Fig. S4. Histone modification in cell-specific FOXA1 regulation.
    • Table S1. Pathway analysis of functional FOXA1 target genes in human cancer cells by Ingenuity.
    • Table S2. Genomic annotation of FOXA1 binding peaks in human cancer cells.
    • Table S3. Whole genome sequencing data for human cancer cells.
    • Table S4. Validation of SNV-introduced gain and loss of FOXA1 binding in human cancer cells.
    • References (32–38)

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