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.

Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

“…This suggests that the liver lincRNA genes evolved more recently and have not yet dispersed their regulatory regions to more distant genomic loci, as appears to have occurred with regulatory elements of liver-expressed protein-coding genes (111). Based on these findings, we can anticipate that liver-expressed lincRNA and protein-coding gene promoters will be enriched for distinct sets of TF motifs, as was found for human lincRNAs (112). Our finding of high liver lincRNA promoter conservation contrasts with other studies reporting conservation of lincRNA promoters either similar to (4) or lower than (25) those of protein-coding gene promoters in other systems.…”

Chromatin environment, transcriptional regulation, and splicing distinguish lincRNAs and mRNAs

“…Whereas in general terms lincRNAs and mRNAs share similar histone marks, such as H3K4me3 in their promoter and H3K36 in the gene body, when comparing expression-matched populations, there are slight differences. Possibly the most striking difference is that H3K9me3-a canonically repressive histone mark-is enriched in the promoters of active lincRNAs (Alam et al 2014) compared to active mRNAs, and that expression of H3K9me3-marked lincRNAs is more tissue-specific than that of lincRNAs lacking H3K9me3. In addition, lincRNAs have fewer transcription factors bound to their promoters than similarly expressed mRNAs.…”

A Comprehensive Characterization of the Function of LincRNAs in Transcriptional Regulation Through Long-Range Chromatin Interactions

“…Both studies revealed that the expression of lincRNAs is regulated by different types of distal regulatory elements, which is similar to the regulation of protein-coding genes with distal regulatory elements. However, the combinatorial patterns of the chromatin states and the transcription factor binding sites in the promoter regions and distal regulatory elements are distinct between the lincRNAs and protein-coding genes64.…”