Strand asymmetry in the distribution of guanines and cytosines, measured by GC 
skew, predisposes DNA sequences toward R-loop formation upon transcription. 
Previous work revealed that GC skew and R-loop formation associate with a core 
set of unmethylated CpG island (CGI) promoters in the human genome. Here, we 
show that GC skew can distinguish four classes of promoters, including three 
types of CGI promoters, each associated with unique epigenetic and gene ontology 
signatures. In particular, we identify a strong and a weak class of CGI 
promoters and show that these loci are enriched in distinct chromosomal 
territories reflecting the intrinsic strength of their protection against DNA 
methylation. Interestingly, we show that strong CGI promoters are depleted from 
the X chromosome while weak CGIs are enriched, a property consistent with the 
acquisition of DNA methylation during dosage compensation. Furthermore, we 
identify a third class of CGI promoters based on its unique GC skew profile and 
show that this gene set is enriched for Polycomb group targets. Lastly, we show 
that nearly 2000 genes harbor GC skew at their 3' ends and that these genes are 
preferentially located in gene-dense regions and tend to be closely arranged. 
Genomic profiling of R-loops accordingly showed that a large proportion of genes 
with terminal GC skew form R-loops at their 3' ends, consistent with a role for 
these structures in permitting efficient transcription termination. Altogether, 
we show that GC skew and R-loop formation offer significant insights into the 
epigenetic regulation, genomic organization, and function of human genes.