Myc-binding-site recognition in the human genome is determined by chromatin context

Large-scale chromatin immunoprecipitation ( ChIP) studies have been effective in unravelling the distribution of DNA-binding transcription factors along eukaryotic genomes(1), but specificity determinants remain elusive. Gene-regulatory regions display distinct histone variants and modifications ( or marks)(2-15). An attractive hypothesis is that these marks modulate protein recognition(16-18), but whether or not this applies to transcription factors remains unknown. Based on large-scale datasets(2,19-21) and quantitative ChIP, we dissect the correlations between 35 histone marks and genomic binding by the transcription factor Myc. Our data reveal a relatively simple combinatorial organization of histone marks in human cells, with a few main groups of marks clustering on distinct promoter populations. A stretch of chromatin bearing high H3 K4/K79 methylation and H3 acetylation ( or 'euchromatic island'), which is generally associated with a pre-engaged basal transcription machinery(12,13), is a strict prerequisite for recognition of any target site by Myc ( whether the consensus CACGTG or an alternative sequence)(22). These data imply that tethering of a transcription factor to restricted chromatin domains is rate-limiting for sequence-specific DNA binding in vivo.