Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts
- Allan M. Gurtan1,
- Arvind Ravi2,
- Peter B. Rahl3,
- Andrew D. Bosson1,4,
- Courtney K. JnBaptiste1,4,
- Arjun Bhutkar1,
- Charles A. Whittaker1,
- Richard A. Young3 and
- Phillip A. Sharp1,4,5
- 1David H. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts 02139, USA;
- 2Harvard-Massachussets Institute of Technology Health Sciences and Technology Program, Cambridge, Massachusetts 02139, USA;
- 3Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA;
- 4Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Abstract
MicroRNAs (miRNAs) are critical to proliferation, differentiation, and development. Here, we characterize gene expression in murine Dicer-null adult mesenchymal stem cell lines, a fibroblast cell type. Loss of Dicer leads to derepression of let-7 targets at levels that exceed 10-fold to 100-fold with increases in transcription. Direct and indirect targets of this miRNA belong to a mid-gestation embryonic program that encompasses known oncofetal genes as well as oncogenes not previously associated with an embryonic state. Surprisingly, this mid-gestation program represents a distinct period that occurs between the pluripotent state of the inner cell mass at embryonic day 3.5 (E3.5) and the induction of let-7 upon differentiation at E10.5. Within this mid-gestation program, we characterize the let-7 target Nr6a1, an embryonic transcriptional repressor that regulates gene expression in adult fibroblasts following miRNA loss. In total, let-7 is required for the continual suppression of embryonic gene expression in adult cells, a mechanism that may underlie its tumor-suppressive function.
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Footnotes
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↵5 Corresponding author
E-mail sharppa{at}mit.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.215376.113.
- Received February 2, 2013.
- Accepted March 27, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press