Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements

Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements

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-re...

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Bibliographic Details
Main Authors: 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., Dalin, Simona, JnBaptiste, Courtney Kenneil, Matthews, Bryan, Yap, Yoon Sing
Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering
Format: Article
Language:en_US
Published: Elsevier 2016
Online Access:http://hdl.handle.net/1721.1/101699
https://orcid.org/0000-0003-0250-0474
https://orcid.org/0000-0003-1465-1691
https://orcid.org/0000-0001-5024-9718
https://orcid.org/0000-0001-9249-8181
https://orcid.org/0000-0002-6534-4774
https://orcid.org/0000-0001-8353-9316
Description
Summary: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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