title: Promoter analysis reveals globally differential regulation of human long non-coding RNA and protein-coding genes.
abstract: Transcriptional regulation of protein-coding genes is increasingly well-understood on a global scale, yet no comparable information exists for long non-coding RNA (lncRNA) genes, which were recently recognized to be as numerous as protein-coding genes in mammalian genomes. We performed a genome-wide comparative analysis of the promoters of human lncRNA and protein-coding genes, finding global differences in specific genetic and epigenetic features relevant to transcriptional regulation. These two groups of genes are hence subject to separate transcriptional regulatory programs, including distinct transcription factor (TF) proteins that significantly favor lncRNA, rather than coding-gene, promoters. We report a specific signature of promoter-proximal transcriptional regulation of lncRNA genes, including several distinct transcription factor binding sites (TFBS). Experimental DNase I hypersensitive site profiles are consistent with active configurations of these lncRNA TFBS sets in diverse human cell types. TFBS ChIP-seq datasets confirm the binding events that we predicted using computational approaches for a subset of factors. For several TFs known to be directly regulated by lncRNAs, we find that their putative TFBSs are enriched at lncRNA promoters, suggesting that the TFs and the lncRNAs may participate in a bidirectional feedback loop regulatory network. Accordingly, cells may be able to modulate lncRNA expression levels independently of mRNA levels via distinct regulatory pathways. Our results also raise the possibility that, given the historical reliance on protein-coding gene catalogs to define the chromatin states of active promoters, a revision of these chromatin signature profiles to incorporate expressed lncRNA genes is warranted in the future.
authors.affiliation: King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia.
authors.forename: Tanvir
authors.initials: T
authors.lastname: Alam
authors.affiliation: King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Medvedeva
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.affiliation: Department of Genome Dynamics, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors.forename: James B
authors.initials: JB
authors.lastname: Brown
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, United States of America; Department of Neurology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Leonard
authors.initials: L
authors.lastname: Lipovich
authors.affiliation: King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Thuwal, Saudi Arabia.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Bajic
mesh_terms: D001665:Binding Sites; D002843:Chromatin / Q000235:genetics; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D011506:Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D014157:Transcription Factors