Distinctive functional regime of endogenous lncRNAs in dark regions of human genome.

>98% of the human genome is composed of noncoding regions and >93% of these noncoding regions are actively transcribed, suggesting their criticality in the human genome. Yet <1% of these regions have been functionally characterized, leaving most of the human genomes in the dark. Here, this study processes petabyte level data and systematically decodes endogenous lncRNAs located in unannotated regions of the human genome and deciphers a distinctive functional regime of lncRNAs hidden in massive RNAseq data. LncRNAs divergently distribute across chromosomes, independent of protein-coding regions. Their transcriptions rarely initiate on promoters through polymerase II, but rather partially on enhancers. Yet conventional enhancer markers (e.g. H3K4me1) only account for a small proportion of lncRNA transcriptions, suggesting alternatively unknown mechanisms initiating the majority of lncRNAs. Furthermore, lncRNA-self regulation also notably contributes to lncRNA activation. LncRNAs regulate broad bioprocesses, including transcription and RNA processing, cell cycle, respiration, response to stress, chromatin organization, post-translational modification, and development. Therefore, lncRNAs functionally govern their own regime distinctive from protein coding genes. This finding establishes a clear framework to comprehend human genome-wide lncRNA-lncRNA and lncRNA-protein coding gene regulations.