Journal
CELL REPORTS
Volume 14, Issue 2, Pages 310-319Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.12.031
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Funding
- NIH [U54-CA112967, R01-GM089903, R01-CA133404, PO1-CA042063, RO1-GM34277, U01-CA184898]
- Koch Institute Support (core) grant from the National Cancer Institute [P30-CA14051]
- National Science Foundation [DB1-0821391]
- Leukemia and Lymphoma Society [5198-09]
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MicroRNAs (miRNAs) regulate diverse biological processes by repressing mRNAs, but their modest effects on direct targets, together with their participation in larger regulatory networks, make it challenging to delineate miRNA-mediated effects. Here, we describe an approach to characterizing miRNA-regulatory networks by systematically profiling transcriptional, post-transcriptional and epigenetic activity in a pair of isogenic murine fibroblast cell lines with and without Dicer expression. By RNA sequencing (RNA-seq) and CLIP (crosslinking followed by immunoprecipitation) sequencing (CLIP-seq), we found that most of the changes induced by global miRNA loss occur at the level of transcription. We then introduced a network modeling approach that integrated these data with epigenetic data to identify specific miRNA-regulated transcription factors that explain the impact of miRNA perturbation on gene expression. In total, we demonstrate that combining multiple genome-wide datasets spanning diverse regulatory modes enables accurate delineation of the downstream miRNA-regulated transcriptional network and establishes a model for studying similar networks in other systems.
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