MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206

Abstract

Terminal differentiation of distinct cell types requires the transcriptional activation of differentiation-specific genes and the suppression of genes associated with the precursor cell. For example, the expression of utrophin (Utrn) is suppressed during skeletal muscle differentiation, and it is replaced at the sarcolemma by the related dystrophin protein. The MyoD transcription factor directly activates the expression of a large number of skeletal muscle genes, but also suppresses the expression of many genes. To characterize a mechanism of MyoD-mediated suppression of gene expression, we investigated two genes that are suppressed in fibroblasts converted to skeletal muscle by MyoD, follistatin-like 1 (Fstl1) and Utrn. MyoD directly activates the expression of a muscle-specific microRNA (miRNA), miR-206, which targets sequences in the Fstl1 and Utrn RNA, and these sequences are sufficient to suppress gene expression in the presence of miR-206. These findings demonstrate that MyoD, in addition to activating muscle-specific genes, induces miRNAs that repress gene expression during skeletal muscle differentiation.

Distinctive patterns of microRNA expression in primary muscular disorders

“…In contrast, overexpression of miRNA-1 in mouse cardiac progenitors has a negative effect on proliferation, where it targets the transcription factor Hand2, involved in myocyte expansion (21). Similar to the heart, miRNA-1 overexpression in cultured skeletal myoblasts promotes skeletal muscle differentiation, as does the related but skeletal muscle-specific miR-206 (18,22) that has also been shown to mediate MyoD-dependent inhibition of follistatin-like-1 and Utrophin genes in myoblasts (23).…”

Bone morphogenetic protein-2 down-regulates miR-206 expression by blocking its maturation process

“…Complementary DNA was synthesized with Omniscript Reverse Transcriptase (RT) (Qiagen) using an oligo (dT) 15 primer. Two microliters of the RT reaction were used for PCR analysis.…”

“…[15]. However, like other RNAs, miRNA expression could potentially be controlled at the post-transcriptional level.…”

MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation

“…In C. elegans and Drosophila, miRNAs have been shown to affect a number of biological processes including developmental timing [5], left/right asymmetric neuronal cell fate [6,7], programmed cell death [8], muscle development [9], and fat metabolism [10]. In mammals, miRNAs have been implicated in a broad range of processes including hematopoietic lineage differentiation, developmental patterning, heart and skeletal muscle differentiation and function, insulin secretion, and immune function [11][12][13][14][15][16][17][18][19][20][21]. miRNAs also appear to have important roles in the mammalian central nervous system (CNS).…”