MicroRNAs are important gene regulators involved in many biological processes, 
including stemness maintenance and cellular reprogramming. Current methods used 
in loss-of-function studies of microRNAs mainly include locked nucleic acid 
(LNA) oligonucleotides and miRZip inhibitors, which have several limitations. 
Due to their unique gene structures and small sizes, there is no efficient or 
simple strategy to knock down or knock out microRNAs or whole microRNA clusters. 
Here, we demonstrate knockdown of the miR-302/367 cluster by using the 
Kruppel-associated box repressor domain fused with specific transcription 
activator-like effectors (TALEs) designed to bind the miR-302/367 cluster 
promoter. We also designed two pairs of TALE nucleases (TALENs) to efficiently 
delete the miR-302/367 cluster in primary human fibroblasts and determined that 
knockout of the miR-302/367 cluster completely blocked induced pluripotent stem 
cell (iPSC) generation. Together, our results demonstrate that TALE-based 
transcriptional repressor and TALENs are two promising approaches for 
loss-of-function studies of microRNA clusters in somatic cells and pluripotent 
stem cells.