title: Let-7 represses Nr6a1 and a mid-gestation developmental program in adult fibroblasts.
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.
authors: David H. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts 02139, USA.
authors: Allan M
authors: AM
authors: Gurtan
authors: Arvind
authors: A
authors: Ravi
authors: Peter B
authors: PB
authors: Rahl
authors: Andrew D
authors: AD
authors: Bosson
authors: Courtney K
authors: CK
authors: JnBaptiste
authors: Arjun
authors: A
authors: Bhutkar
authors: Charles A
authors: CA
authors: Whittaker
authors: Richard A
authors: RA
authors: Young
authors: Phillip A
authors: PA
authors: Sharp
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1 / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D035683:MicroRNAs; C539954:Nr6a1 protein, mouse; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; C542687:mirnlet7 microRNA, mouse; C031192:oncofetal antigens; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
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