Regulation of cardiac microRNAs by cardiac microRNAs.
Regulation of cardiac microRNAs by cardiac microRNAs.
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DOI：
10.1161/circresaha.113.300975
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发表时间：
2013-06-21
影响因子：
20.1
通讯作者：
Dorn GW 2nd
中科院分区：
文献类型：
--
作者：
Matkovich SJ;Hu Y;Dorn GW 2nd
MicroRNAs modestly suppress their direct mRNA targets and these direct effects are amplified by modulation of gene transcription pathways. Consequently, indirect mRNA modulatory effects of microRNAs to increase or decrease mRNAs greatly outnumber direct target suppressions. Because microRNAs are products of transcription, the potential exists for microRNAs that regulate transcription to regulate other microRNAs. Determine if cardiac-expressed microRNAs regulate expression of other cardiac microRNAs, and measure the impact of microRNA-mediated microRNA regulation on indirect regulation of non-target mRNAs. Transgenic expression of pre-microRNAs was used to generate mouse hearts expressing 6-16 fold normal levels of miR-143, miR-378, and miR-499. Genome-wide mRNA and microRNA signatures were established using deep sequencing; expression profiles provoked by each microRNA were defined. miR-143 suppressed its direct cardiac mRNA target hexokinase 2, but exhibited little indirect target regulation and did not regulate other cardiac microRNAs. Both miR-378 and miR-499 indirectly regulated hundreds of cardiac mRNAs and 15-30 cardiac microRNAs. MicroRNA overexpression did not alter normal processing of either transgenic or endogenous cardiac microRNAs, and microRNA-mediated regulation of other microRNAs encoded within parent genes occurred in tandem with parent mRNAs. MicroRNA regulation by miR-378 and miR-499 was stimulus-specific, and contributed to observed mRNA downregulation. MicroRNAs that modulate cardiac transcription can indirectly regulate other microRNAs. Transcriptional modulation by microRNAs, and microRNA-mediated microRNA regulation, help explain how small direct effects of microRNAs are amplified to generate striking phenotypes.
