Deciphering the Functional Long Non‐Coding RNAs Derived from MicroRNA Loci

Albeit the majority of eukaryotic genomes can be pervasively transcribed to a diverse population of lncRNAs and various subtypes of lncRNA are discovered. However, the genome‐wide study of miRNA‐derived lncRNAs is still lacking. Here, it is reported that over 800 miRNA gene‐originated lncRNAs (molncRNAs) are generated from miRNA loci. One of them, molnc‐301b from miR‐301b and miR‐130b, functions as an “RNA decoy” to facilitate dissociation of the chromatin remodeling protein SMARCA5 from chromatin and thereby sequester transcription and mRNA translation. Specifically, molnc‐301b attenuates erythropoiesis by mitigating the transcription of erythropoietic and translation‐associated genes, such as GATA1 and FOS. In addition, a useful and powerful CRISPR screen platform to characterize the biological functions of molncRNAs at large‐scale and single‐cell levels is established and 29 functional molncRNAs in hematopoietic cells are identified. Collectively, the focus is on miRNA‐derived lncRNAs, deciphering their landscape during normal hematopoiesis, and comprehensively evaluating their potential roles. This work comprehensively characterizes over 860 miRNA gene‐originated lncRNAs (molncRNAs) and clarifies their landscape during erythropoiesis. One of them, molnc‐301b, regulates erythroid differentiation independent of its cognate miRNAs by coordinating the transcription and translation efficiency of key erythroid regulators. Finally, a screening platform using CRISPR‐based single‐cell RNA sequencing is established to characterize functional molncRNAs at large‐scale and single‐cell levels.