We present the first genome-wide demonstration of a significant difference in sequence characteristics between the promoters of human lncRNA and protein-coding genes, suggesting distinct regulation of the two gene groups. In view of the frequent bidirectionality of human promoters that simultaneously give rise to protein-coding and lncRNA genes [63], the distinctions we find are all the more remarkable, since bidirectional promoters are counted by our approach as both protein-coding and lncRNA. We speculate that specific TFs may function as network nodes that not only accept directional edges from regulatory lncRNAs, but also serve as network hubs that extend multiple new directional edges toward other lncRNA genes whose promoters contain their cognate TFBSs. In particular, our study, for the first time, suggests that specific NHRs - members of the nuclear receptor family, which are already known to be targeted by lncRNA-protein interactions that join lncRNAs and NHRs in ribonucleoprotein complexes – in turn, may regulate lncRNA transcription through promoter binding. Among the other TFs we considered, GATA3, ARID3A, and MEF2A have the singular distinction of being significantly supported by all three
