Unbiased Mapping of Transcription Factor Binding Sites along Human Chromosomes 21 and 22 Points to Widespread Regulation of Noncoding RNAs

Simon Cawley, Stefan Bekiranov, Huck H Ng, Philipp Kapranov, Edward A Sekinger, Dione Kampa, Antonio Piccolboni, Victor Sementchenko, Jill Cheng, Alan J Williams, Raymond Wheeler, Brant Wong, Jorg Drenkow, Mark Yamanaka, Sandeep Patel, Shane Brubaker, Hari Tammana, Gregg Helt, Kevin Struhl, Thomas R Gingeras

Using high-density oligonucleotide arrays representing essentially all nonrepetitive sequences on human chromosomes 21 and 22, we map the binding sites in vivo for three DNA binding transcription factors, Sp1, cMyc, and p53, in an unbiased manner. This mapping reveals an unexpectedly large number of transcription factor binding site (TFBS) regions, with a minimal estimate of 12,000 for Sp1, 25,000 for cMyc, and 1600 for p53 when extrapolated to the full genome. Only 22% of these TFBS regions are located at the 5' termini of protein-coding genes while 36% lie within or immediately 3' to well-characterized genes and are significantly correlated with noncoding RNAs. A significant number of these noncoding RNAs are regulated in response to retinoic acid, and overlapping pairs of protein-coding and noncoding RNAs are often coregulated. Thus, the human genome contains roughly comparable numbers of protein-coding and noncoding genes that are bound by common transcription factors and regulated by common environmental signals.