Defining Transcriptional Regulatory Mechanisms for Primary let-7 miRNAs

Abstract

<div><p>The <i>let-7</i> family of miRNAs have been shown to control developmental timing in organisms from <i>C</i>. <i>elegans</i> to humans; their function in several essential cell processes throughout development is also well conserved. Numerous studies have defined several steps of post-transcriptional regulation of <i>let-7</i> production; from pri-miRNA through pre-miRNA, to the mature miRNA that targets endogenous mRNAs for degradation or translational inhibition. Less-well defined are modes of transcriptional regulation of the pri-miRNAs for <i>let-7</i>. <i>let-7</i> pri-miRNAs are expressed in polycistronic fashion, in long transcripts newly annotated based on chromatin-associated RNA-sequencing. Upon differentiation, we found that some <i>let-7</i> pri-miRNAs are regulated at the transcriptional level, while others appear to be constitutively transcribed. Using the Epigenetic Roadmap database, we further annotated regulatory elements of each polycistron identified putative promoters and enhancers. Probing these regulatory elements for transcription factor binding sites identified factors that regulate transcription of <i>let-7</i> in both promoter and enhancer regions, and identified novel regulatory mechanisms for this important class of miRNAs.</p></div