Abstract
The let-7 family of miRNAs have been shown to control developmental timing in organisms from C. elegans 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 let-7 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 let-7. let-7 pri-miRNAs are expressed in polycistronic fashion, in long transcripts newly annotated based on chromatin-associated RNA-sequencing. Upon differentiation, we found that some let-7 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 let-7 in both promoter and enhancer regions, and identified novel regulatory mechanisms for this important class of miRNAs.
Highlights
The let-7 family of miRNAs were first identified in C. elegans as a single heterochronic factor controlling developmental timing[1, 2]
Summary ENCODE and Roadmap gene expression data, ChIP-Seq mapping data, and ChromHMM chromatin state prediction were accessed and visualized using the UCSC genome browser and the WashU Epigenome Browser43,44. These tools were used to import and visualize Chromatin-associated RNA-seq reads from Patterson et al and miRNA gene transcripts in cells lacking DGCR8 from Chang et al6,25.Transcription factor binding site predictions were performed with the ORCA Toolkit web server, and with the MEME suite of motif analysis applications45,46
The ENCODE and Epigenetic Roadmap datasets, with accession numbers listed in Tables 1 and 2, contain mapped reads from various gene expression and ChIP-sequencing experiments performed on a panel of cell lines and cell types isolated from primary human tissue
Summary
The let-7 family of miRNAs were first identified in C. elegans as a single heterochronic factor controlling developmental timing[1, 2]. Since this family of miRNAs has been shown to play somewhat equivalent roles in all bilaterian organisms, and the let-7s were the first miRNAs identified in humans[1, 3]. As with other miRNAs, the initial pri-let-7 transcripts are first transcribed by RNA polymerase II, processed via the canonical pathway through the pre-miRNA stage generated by the action of Drosha/DGCR8. The pre-miRNA is processed in the cytoplasm by Dicer to generate the mature version of the miRNA[8,9,10]. LIN28A and LIN28B are RNA binding proteins that regulate several of these processing steps to control levels of PLOS ONE | DOI:10.1371/journal.pone.0169237 January 4, 2017
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