Mechanistic insights into the transcription-mediated roles of non-coding RNAs in gene regulation

A large portion of the genome is transcribed into noncoding RNAs (ncRNAs). Although initially thought to be functionally insignificant, many ncRNAs are now recognized as important regulators of gene expression. Among these, long non-coding RNAs (lncRNAs), transcripts longer than 200 bases with almost no coding potential, and enhancer RNAs (eRNAs), which are transcribed from regulatory regions on the genome, can regulate nearby genes through diverse cis-acting mechanisms. This review discusses six primary transcription-dependent regulatory mechanisms: transcription-dependent activation, chromatin remodeling, R-loop formation, transcriptional condensate formation, DNA looping, and transcriptional interference. Throughout the review, multiple examples of lncRNAs and eRNAs are presented to illustrate their diverse regulatory functions. lncRNAs often function through the act of transcription itself or by recruiting chromatin-modifying complexes, whereas eRNAs more commonly require their RNA transcript for condensate formation or enhancer-promoter looping. However, the contexts determining the preferred mechanisms remain unclear, and individual transcripts may function through multiple mechanisms. Further advances are needed to distinguish transcription-mediated from RNA-mediated gene regulation.