[en] 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.
Biochemistry, biophysics & molecular biology
Author, co-author :
Bouvy-Liivrand, Maria ✱; University of Eastern Finland > School of Medicine
Hernandez de Sande, Ana ✱; University of Eastern Finland
Pölönen, Petri; University of Eastern Finland
Mehtonen, Juha; University of Eastern Finland
Vuorenmaa, Tapio; University of Eastern Finland
Niskanen, Henri; University of Eastern Finland > A. I. Virtanen Institute
Sinkkonen, Lasse ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Kaikkonen, Minna; University of Eastern Finland > A. I. Virtanen Institute
Heinäniemi, Merja; University of Eastern Finland > School of Medicine
✱ These authors have contributed equally to this work.
External co-authors :
Analysis of primary microRNA loci from nascent transcriptomes reveals regulatory domains governed by chromatin architecture