Transcriptional targeting by microRNA-polycomb complexes: a novel route in cell fate determination

Abstract

Advances in the understanding of the epigenetic events underlying the regulation of developmental genes expression and cell lineage commitment are revealing novel regulatory networks. These also involve distinct components of the epigenetic pathways, including chromatin histone modification, DNA methylation, repression by polycomb complexes and microRNAs. Changes in chromatin structure, DNA methylation status and microRNA expression levels represent flexible, reversible and heritable mechanisms for the maintenance of stem cell states and cell fate decisions. We recently provided novel evidence showing that microRNAs, besides determining the post-transcriptional gene silencing of their targets, also bind to evolutionarily conserved complementary genomic seed-matches present on target gene promoters. At these sites, microRNAs can function as a critical interface between chromatin remodeling complexes and the genome for transcriptional gene silencing. Here, we discuss our novel findings supporting a role of the transcriptional chromatin targeting by polycomb-microRNA complexes in lineage fate determination of human hematopoietic cells.

Figure 1. Transcriptional regulation of the NFI-A gene by a miR-223/Polycomb/RISC complex governs hematopoietic progenitors cell fate. (A) The undifferentiated hematopoietic progenitors display bivalent nucleosomal histone modifications on the NFI-A gene promoter where H3K4me3 activating mark (green) and H3K27me3 repressive mark (red) are balanced. CpG islands are not methylated (white small circles). The expression levels of both miR-223 and NFI-A mRNA are low. (B) Upon granulocytic differentiation the expression of miR-223 markedly increases and bivalent domains are resolved: the repressive H3K27me3 mark accumulates whereas the activating H3K4me3 decreases and methylated CpGs increase (black small circles). This is due to the aggregation on the promoter of the NFI-A gene of a ribonuclear complex involving miR-223, the RISC components Ago1 and Dicer1 and the PcG proteins YY1 and Suz12. The complex is driven by miR-223 to miR-complementary sequences on the NFI-A promoter. The result is transcriptional repression of NFI-A gene. (C) During erythropoiesis the expression of miR-223 decreases and bivalent domains are resolved in the opposite direction. The NFI-A gene promoter acquires a “permissive chromatin status,” with high levels of the activating histone marks H3K4me3, unmethylated CpGs and low levels of the repressive histone mark H3K27me3. NFI-A expression is high. Gray spheres indicate the octamer of nucleosomal histones with the double strand DNA wrapped around them.