Promoter Analysis Reveals Globally Differential Regulation of Human Long Non-Coding RNA and Protein-Coding Genes

• Published in: PloS one Vol. 9; no. 10; p. e109443
• Main Authors: Alam, Tanvir, Medvedeva, Yulia A., Jia, Hui, Brown, James B., Lipovich, Leonard, Bajic, Vladimir B.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.10.2014; Public Library of Science (PLoS)
• Subjects: BASIC BIOLOGICAL SCIENCES; Binding Sites; Biology and life sciences; Cells (Biology); Chromatin; Chromatin - genetics; Comparative analysis; Computer and Information Sciences; Computer applications; Deoxyribonuclease; Deoxyribonucleic acid; DNA; DNA methylation; DNA transcription; Epigenetic inheritance; Epigenetics; Evolution & development; Feedback loops; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genetics; Genome, Human; Genomes; Genomics; Humans; Hypotheses; long non-coding RNAs; Medicine; Non-coding RNA; Promoter Regions, Genetic; Promoters; Protein Binding; Proteins; Proteins - genetics; Research and Analysis Methods; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Messenger - genetics; RNA-protein interactions; Science; sequence motif analysis; Transcription (Genetics); transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Saudi Arabia; Detroit Michigan; United States > US; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109443

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.