Localization is the key to action: regulatory peculiarities of lncRNAs

To understand the transcriptomic profile of an individual cell in a multicellular organism, we must comprehend its surrounding environment and the cellular space where distinct molecular stimuli responses are located. Contradicting the initial perception that RNAs were nonfunctional and that only a few could act in chromatin remodeling, over the last few decades, research has revealed that they are multifaceted, versatile regulators of most cellular processes. Among the various RNAs, long non-coding RNAs (LncRNAs) regulate multiple biological processes and can even impact cell fate. In this sense, the subcellular localization of lncRNAs is the primary determinant of their functions. It affects their behavior by limiting their potential molecular partner and which process it can affect. The fine-tuned activity of lncRNAs is also tissue-specific and modulated by their cis and trans regulation. Hence, the spatial context of lncRNAs is crucial for understanding the regulatory networks by which they influence and are influenced. Therefore, predicting a lncRNA's correct location is not just a technical challenge but a critical step in understanding the biological meaning of its activity. Hence, examining these peculiarities is crucial to researching and discussing lncRNAs. In this review, we debate the spatial regulation of lncRNAs and their tissue-specific roles and regulatory mechanisms. We also briefly highlight how bioinformatic tools can aid research in the area.