BACKGROUND: High-occupancy target (HOT) regions are compact genome loci occupied 
by many different transcription factors (TFs). HOT regions were initially 
defined in invertebrate model organisms, and we here show that they are a 
ubiquitous feature of the human gene-regulation landscape.
RESULTS: We identified HOT regions by a comprehensive analysis of ChIP-seq data 
from 96 DNA-associated proteins in 5 human cell lines. Most HOT regions 
co-localize with RNA polymerase II binding sites, but many are not near the 
promoters of annotated genes. At HOT promoters, TF occupancy is strongly 
predictive of transcription preinitiation complex recruitment and moderately 
predictive of initiating Pol II recruitment, but only weakly predictive of 
elongating Pol II and RNA transcript abundance. TF occupancy varies 
quantitatively within human HOT regions; we used this variation to discover 
novel associations between TFs. The sequence motif associated with any given 
TF's direct DNA binding is somewhat predictive of its empirical occupancy, but a 
great deal of occupancy occurs at sites without the TF's motif, implying 
indirect recruitment by another TF whose motif is present.
CONCLUSIONS: Mammalian HOT regions are regulatory hubs that integrate the 
signals from diverse regulatory pathways to quantitatively tune the promoter for 
RNA polymerase II recruitment.