Genome wide relationship between histone H3 lysine 4 mono- and tri-methylation and transcription factor binding

Abstract

We characterized the relationship of H3K4me1 and H3K4me3 at distal and proximal regulatory elements by comparing ChIP-seq profiles for these histone modifications and for two functionally different transcription factors: STAT1 in the immortalized HeLa S3 cell line, with and without interferon-γ (IFNG) stimulation, and FOXA2 in mouse adult liver tissue. In unstimulated and stimulated HeLa cells we respectively determined 270 and 300 thousand H3K4me1-enriched regions, and 54 and 76 thousand H3K4me3-enriched regions. In mouse adult liver we determined 227 and 35 thousand H3K4me1 and H3K4me3 regions. Seventy five percent of the 70 thousand STAT1 binding sites in stimulated HeLa cells and 87% of the 11 thousand Foxa2 sites in mouse liver were distal to known gene TSSs; in both tissues, ~83% of these distal sites were associated with at least one of the two histone modifications, and H3K4me1 was associated with over 96% of marked distal sites. After filtering against predicted TSSs, 51% of 27k marked distal IFNG-stimulated STAT1 binding sites, but 95% of 5.8k marked distal Foxa2 sites, were associated with H3K4me1 only. Results for HeLa cells generated additional insights into transcriptional regulation involving STAT1. STAT1 binding was associated with 25% of all H3K4me1 regions in stimulated HeLa cells, suggesting that a single transcription factor can interact with an unexpectedly large fraction of regulatory regions. Strikingly, for a large majority of the locations of stimulated STAT1 binding, the dominant H3K4me1/me3 combinations were established before activation, suggesting mechanisms independent of IFNG stimulation and high-affinity STAT1 binding.

• Foxa2
• H3K4me1
• H3K4me3
• STAT1
• histone