Analysis of primary microRNA loci from nascent transcriptomes reveals regulatory domains governed by chromatin architecture
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CitationBouvy-Liivrand Maria. Hernández de Sande Ana. Pölönen Petri. Mehtonen Juha. Vuorenmaa Tapio. Niskanen Henri. Sinkkonen Lasse. Unelma Kaikkonen Minna. Heinäniemi Merja. (2017). Analysis of primary microRNA loci from nascent transcriptomes reveals regulatory domains governed by chromatin architecture. NUCLEIC ACIDS RESEARCH, 45 (17) , 9837-9849. 10.1093/nar/gkx680.
Changes in mature microRNA (miRNA) levels that occur downstream of signaling cascades play an important role during human development and disease. However, the regulation of primary microRNA (pri-miRNA) genes remains to be dissected in detail. To address this, we followed a data-driven approach and developed a transcript identification, validation and quantification pipeline for characterizing the regulatory domains of pri-miRNAs. Integration of 92 nascent transcriptomes and multilevel data from cells arising from ecto-, endo- and mesoderm lineages reveals cell type-specific expression patterns, allows fine-resolution mapping of transcription start sites (TSS) and identification of candidate regulatory regions. We show that inter- and intragenic pri-miRNA transcripts span vast genomic regions and active TSS locations differ across cell types, exemplified by the mir-29a∼29b-1, mir-100∼let-7a-2∼125b-1 and miR-221∼222 clusters. Considering the presence of multiple TSS as an important regulatory feature at miRNA loci, we developed a strategy to quantify differential TSS usage. We demonstrate that the TSS activities associate with cell type-specific super-enhancers, differential stimulus responsiveness and higher-order chromatin structure. These results pave the way for building detailed regulatory maps of miRNA loci.