Transcription factor co-occupancy and histone methylation determine tissue specific FoxA2 target gene expression

An understanding of how transcription factors regulate distinct sets of target genes in different tissues is emerging. The liver and pancreas share a common origin and coexpress several transcription factors, including the pioneer factor FoxA2 that is central to the development of both tissues. Here, we globally identify binding sites for FoxA2 in islets and liver, for Pdx1 in islets, and for Hnf4a in liver. Combining these data with transcriptome expression and global H3K4me1 and H3K4me3 localization data, we show that tissue-specific FoxA2 recruitment and histone methylation contribute to tissuespecific FoxA2 target gene expression. Further we show that, although genes associated with FoxA2 sites co-occupied by Pdx1 or Hnf4a are not more likely to be expressed, they have significantly increased tissue-specific expression. Finally, we demonstrate that the spacing of flanking H3K4me1 modifications at co-occupied sites is increased, indicating the proximal chromatin associated with these sites is more open.