Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements
Author(s)Gurtan, Allan M.; JnBaptiste, Courtney K.; Bosson, Andrew; Milani, Pamela; Matthews, Bryan J.; Yap, Yoon S.; Sharp, Phillip A.; Fraenkel, Ernest; Gosline, Sara Jane Calafell; Gurtan, Allan M.; Sharp, Phillip A.; Dalin, Simona; JnBaptiste, Courtney Kenneil; Matthews, Bryan; Yap, Yoon Sing; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MIT
Gosline, Sara J.C., Allan M. Gurtan, Courtney K. JnBaptiste, Andrew Bosson, Pamela Milani, Simona Dalin, Bryan J. Matthews, Yoon S. Yap, Phillip A. Sharp, and Ernest Fraenkel. “Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-Transcriptional, and Histone Modification Measurements.” Cell Reports 14, no. 2 (January 2016): 310–19.
Final published version