The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r.
The H19 large intergenic non-coding RNA (lincRNA) is one of the most highly abundant and conserved transcripts in mammalian development, being expressed in both embryonic and extra-embryonic cell lineages, yet its physiological function is unknown. Here we show that miR-675, a microRNA (miRNA) embedded in H19's first exon, is expressed exclusively in the placenta from the gestational time point when placental growth normally ceases, and placentas that lack H19 continue to grow. Overexpression of miR-675 in a range of embryonic and extra-embryonic cell lines results in their reduced proliferation; targets of the miRNA are upregulated in the H19 null placenta, including the growth-promoting insulin-like growth factor 1 receptor (Igf1r) gene. Moreover, the excision of miR-675 from H19 is dynamically regulated by the stress-response RNA-binding protein HuR. These results suggest that H19's main physiological role is in limiting growth of the placenta before birth, by regulated processing of miR-675. The controlled release of miR-675 from H19 may also allow rapid inhibition of cell proliferation in response to cellular stress or oncogenic signals.
Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.
Andrew
A
Keniry
David
D
Oxley
Paul
P
Monnier
Michael
M
Kyba
Luisa
L
Dandolo
Guillaume
G
Smits
Wolf
W
Reik
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015536:Down-Regulation; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy; D034622:RNA Interference; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D051959:ELAV Proteins; C094335:H19 long non-coding RNA; C574758:MIRN675 microRNA, mouse; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D017526:Receptor, IGF Type 1; C509781:Dicer1 protein, mouse; C513400:Drosha protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases