A group of tissue‐specific microRNAs contribute to the silencing of CUX1 in different cell lineages during development

Abstract Cut‐like homeobox 1 (CUX1) is a highly conserved homeoprotein that functions as a transcriptional repressor of genes specifying terminal differentiation. We previously showed that liver‐specific microRNA‐122 (miR‐122) regulates the timing of liver development by silencing CUX1 post‐transcriptionally. Since the CUX1 protein is expressed in a subset of embryonic tissues, we hypothesized that it is regulated by specific microRNAs (miRNAs) in each cell type during development. Using a large‐scale screening method, we identified ten tissue‐specific miRNAs from different cell lineages that directly targeted CUX1. An analysis of the interaction between heart‐specific microRNA‐208a (miR‐208a) and CUX1 in the hearts of developing mouse embryos and in P19CL6 cells undergoing cardiac differentiation indicated that CUX1 is regulated by miR‐208a during heart development and cardiomyocyte differentiation. Functional analysis of miR‐208a in P19CL6 cells using lentiviral‐mediated over‐expression showed that it regulates the transition between cellular proliferation and differentiation. These results suggest that these tissue‐specific miRNAs might play a common role in timing the progression of terminal differentiation of different cell lineages, possibly by silencing the differentiation repressor CUX1.