Although regulation of histone methylation is believed to contribute to 
embryonic stem cell (ESC) self-renewal, the mechanisms remain obscure. We show 
here that the histone H3 trimethyl lysine 4 (H3K4me3) demethylase, KDM5B, is a 
downstream Nanog target and critical for ESC self-renewal. Although KDM5B is 
believed to function as a promoter-bound repressor, we find that it 
paradoxically functions as an activator of a gene network associated with 
self-renewal. ChIP-Seq reveals that KDM5B is predominantly targeted to 
intragenic regions and that it is recruited to H3K36me3 via an interaction with 
the chromodomain protein MRG15. Depletion of KDM5B or MRG15 increases intragenic 
H3K4me3, increases cryptic intragenic transcription, and inhibits 
transcriptional elongation of KDM5B target genes. We propose that KDM5B 
activates self-renewal-associated gene expression by repressing cryptic 
initiation and maintaining an H3K4me3 gradient important for productive 
transcriptional elongation.