Cells lacking miRNAs (bottom) do not differentiate into muscle (right).

Muscle-specific miRNAs can induce differentiation at least in part by depleting DNA polymerase α mRNA, according to Kim et al. (page 677). Although other factors are also involved in the differentiation process, obliterating the DNA replication machinery is a novel means to bring the cell cycle to a halt in differentiating cells.

Kim et al. started with the miR-1, -133, and -206 miRNAs because they are known to be expressed in muscle and heart. Expression of all three increased when C2C12 myoblast precursors were induced to differentiate into muscle by the withdrawal of serum. In fact, expression of miR-206 was sufficient to induce differentiation even in serum. Conversely, blocking its expression dramatically reduced the fraction of cells that exited the cell cycle and differentiated.

To identify targets of these miRNAs, the researchers looked at microarrays. Several genes were down-regulated in response to the miRNAs and contained target sites complementary to the miRNAs. Some of these targets remain somewhat mysterious as to their differentiation function, but the one that stood out was was DNA polα. The expression of miR-206 alone was sufficient to cleave DNA polα mRNA and decrease levels of the polymerase protein. Other differentiation factors appear to take over later, but it appears that miR-206 is important for immediate down-regulation of DNA polα.

A key question is whether other differentiation-promoting miRNAs target the DNA replication machinery, as miRNAs have been found to be involved in differentiation of several other postmitotic cell types. The C2C12 cells used in the current study can also differentiate into adipocytes. The researchers are therefore currently working to see if any of the adipocyte-specific miRNAs also hit DNA replication or cell cycle genes.