FIGURE 3.

MicroRNAs interact with transcription factors and epigenetic regulators to control aNSC proliferation and differentiation. (A) The transcriptional repressor REST serves as regulatory hub for several miRNAs, including pro-neural miR-9 and miR-124. REST represses expression of miR-9 and miR-124, which in turn interfere with the activity of the Rest complex by targeting Rest or its cofactors CoRest and Scp1. (B) Another transcription factor interacting with miRNAs in the context of NSC self-renewal and differentiation is TLX. TLX has a direct repressive effect on miR-9 expression and also inhibits expression of miR-137 via recruiting the histone demethylase LSD1. The activity of TLX itself is regulated by miR-9 as well as let-7, which both target Tlx, and miR-137, which targets Lsd1. (C–D) miRNAs often interact with epigenetic regulators, such as mediators of DNA methylation and histone modifiers. (C) Expression of miR-184 and miR-195 is suppressed by binding of the methyl-CpG-binding protein MBD1 to their genomic loci. miRNA-195, in turn, binds to Mbd1 mRNA forming a negative feedback loop, while miR-184 targets Numbl. (D) MECP2 cooperates with the neural progenitor transcription factor SOX2 to repress miR-137 expression. miRNA-137 may regulate global gene transcription through repressing the expression of histone modifiers, i.e., EZH2, which induces repressive H3K27 trimethylation (me3) marks, and LSD1, which erases activating H3K4me3 marks. LSD1 and MECP2 are also recruited by the REST/CoREST complex, thus forming another node through which the miRNAs discussed here may cross talk with each other. For sake of simplicity, these interactions were not depicted here. For a detailed review on the cross talk between miRNAs and epigenetic regulators, see Jobe et al. (2012).