Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Authors: Rau, Frederique; Freyermuth, Fernande; Fugier, Charlotte; Villemin, Jean-Philippe; Fischer, Marie-Christine; Jost, Bernard; Dembele, Doulaye; Gourdon, Genevieve; Nicole, Annie; Duboc, Denis; Wahbi, Karim; Day, John W.; Fujimura, Harutoshi; Takahashi, Masanori P.; Auboeuf, Didier; Dreumont, Natacha; Furling, Denis; Charlet-Berguerand, Nicolas
Abstract
Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR-1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium-and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons.
Selective microRNA uridylation by Zcchc6 (TUT7) and Zcchc11 (TUT4)
NUCLEIC ACIDS RESEARCH
Authors: Thornton, James E.; Du, Peng; Jing, Lili; Sjekloca, Ljiljana; Lin, Shuibin; Grossi, Elena; Sliz, Piotr; Zon, Leonard I.; Gregory, Richard I.
Abstract
Recent small RNA sequencing data has uncovered 3' end modification of mature microRNAs (miRNAs). This non-templated nucleotide addition can impact miRNA gene regulatory networks through the control of miRNA stability or by interfering with the repression of target mRNAs. The miRNA modifying enzymes responsible for this regulation remain largely uncharacterized. Here we describe the ability for two related terminal uridyl transferases (TUTases), Zcchc6 (TUT7) and Zcchc11 (TUT4), to 3' mono-uridylate a specific subset of miRNAs involved in cell differentiation and Homeobox (Hox) gene control. Zcchc6/11 selectively uridylates these miRNAs in vitro, and we biochemically define a bipartite sequence motif that is necessary and sufficient to confer Zcchc6/11 catalyzed uridylation. Depletion of these TUTases in cultured cells causes the selective loss of 3' mono-uridylation of many of the same miRNAs. Upon TUTase-dependent loss of uridylation, we observe a concomitant increase in non-templated 3' mono-adenylation. Furthermore, TUTase inhibition in Zebrafish embryos causes developmental defects and aberrant Hox expression. Our results uncover the molecular basis for selective miRNA mono-uridylation by Zcchc6/11, highlight the precise control of different 3' miRNA modifications in cells and have implications for miRNA and Hox gene regulation during development.
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