The Rodent-Specific MicroRNA Cluster within the Sfmbt2 Gene Is Imprinted and Essential for Placental Development

Abstract

MicroRNAs (miRNAs) represent small noncoding RNAs that are involved in physiological and developmental processes by posttranscriptionally inhibiting gene expression. One of the largest miRNA clusters in mice is located in intron 10 of the Sfmbt2 gene, containing 72 miRNA precursor sequences. In this study, we generated mice lacking the entire Sfmbt2 miRNA cluster to elucidate its functions during development. The Sfmbt2 miRNAs were expressed predominantly from the paternal allele in the placenta, as is the host Sfmbt2 gene. Loss of the paternal allele resulted in severely impaired development of the placenta, especially the spongiotrophoblast layer, and frequent lethality or defects of fetuses. The predicted target sequences of the miRNAs and gene expression analysis defined at least nine putative target genes, which function as tumor suppressors or apoptosis inducers. Our study has provided experimental evidence for the indispensable roles of placental miRNAs in trophoblast proliferation and thus fetal development.

CRISPR/Cas9 editing reveals novel mechanisms of clustered microRNA regulation and function

“…Further studies improved the efficiency 19 – 21 . In vivo , the CRISPR/Cas9 platform was used to delete a 53-kb fragment and generate knockout mice to elucidate the function of the largest miRNAs cluster in mice 22 , while the first miRNA double knockout mice using the CRISPR/Cas9 system have also been reported 23 . Recently, a robust approach to establish a multiplex system to achieve targeting of entire miRNA families was developed 24 .…”

Lost in translation

“…The largest clusters of microRNAs in the human and mouse genomes are imprinted. These include a cluster of maternally expressed microRNAs (C14MC) present in all eutherian mammals [ 27 ] and the paternally expressed C19MC cluster of primates [ 71 , 72 ] and Sfmbt2 cluster of muroid rodents [ 73 ]. The maternally expressed H19 long noncoding RNA is not only the substrate for the production of miR-675 but also acts as a competing endogenous RNA (ceRNA) or ‘molecular sponge’ for absorbing other microRNAs [ 74 , 75 ].…”

Placental imprinting: Emerging mechanisms and functions

“…Thus, SFMBT2 may be particularly important for genomic stability in trophoblast, in which repetitive regions are hypomethylated [71]. Intriguingly, the Sfmbt2 gene also contains a large cluster of micro-RNA (miRNA) genes within intron 10, which are also imprinted in placenta [72]. Transgenic mice generated by ablating the entire miRNA cluster had an extremely underdeveloped placental junctional zone, foetal growth restriction, and higher rates of foetal demise [72].…”